Introduction Jun Cui Pages Autophagy Regulation of Mammalian Immune Cells Wenzhuo He, Wenjing Xiong, Xiaojun Xia Pages Autophagy in Plant Immunity Hong-Yun Zeng, Ping Zheng, Ling-Yan Wang, He-Nan Bao, Sunil Kumar Sahu, Nan Yao Pages Autophagy Regulation of Bacterial Pathogen Invasion Yuqing Lei, Huihui Li, Kefeng Lu Pages Autophagy and Viral Infection Jingrong Mao, Eena Lin, Lian He, Jiaming Yu, Peng Tan, Yubin Zhou Pages The Interplay Between Pattern Recognition Receptors and Autophagy in Inflammation Yun Zhu, Jian Deng, Mei-Ling Nan, Jing Zhang, Akinkunmi Okekunle, Jiang-Yuan Li et al.

Pages Regulation of Inflammasome by Autophagy Tao Liu Pages The Cross-Regulation Between Autophagy and Type I Interferon Signaling in Host Defense Shouheng Jin Pages Selective Autophagy Regulates Innate Immunity Through Cargo Receptor Network Yaoxing Wu, Jun Cui Pages Autophagy and Immune-Related Diseases Peng Tan, Youqiong Ye, Jingrong Mao, Lian He Pages Targeting Autophagy with Small-Molecule Modulators in Immune-Related Diseases Lan Zhang, Bo Liu Pages Back to top.

About this book This book discusses novel concepts and discoveries concerning the regulation of innate immunity by autophagy and autophagy-related proteins.

Keywords autophagy innate immunity type I interferon signaling inflammation cargo receptor. Editors and Affiliations School of Life Sciences, Sun Yat-sen University, Guangzhou, China Jun Cui Back to top.

About the editor Dr. Publish with us Policies and ethics. Access via your institution. search Search by keyword or author Search. Navigation Find a journal Publish with us Track your research. pro-IL-1 produced by inflammasomes, or recycling the inflammasome components themselves e. NLRP3, AIM2 and ASC Alternatively, autophagy can also indirectly prevent activation of inflammasomes, by breaking down damaged mitochondria to prevent them from releasing inflammasome-activating ligands such as mitochondrial DNA mtDNA and ROS.

Indeed, activation of MAVS at the membrane of damaged mitochondria has recently been shown to induce autophagy through direct interaction with LC3, which leads to removal of the deleterious organelle Accordingly, cells deficient in the autophagy protein Atg5 accumulate damage organelles and consequently, exhibit augmented production of type I IFNs The awarding of the Nobel Prize in Physiology or Medicine to Yoshinori Ohsumi, who discovered the mechanisms of autophagy, reflects growing appreciation for the paramount role of this cellular process in health and disease.

Nevertheless, recent advances in this field suggest that we are only just beginning to elucidate the interplay between autophagy and innate immune signaling pathways. Levine B. Autophagy in the pathogenesis of disease. Mizushima N. et al. Autophagy fights disease through cellular self-digestion.

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Download references. This work was supported by a research grant from the National Science Funding of China, Grant and YBDCMC Grant LCZXKF-XY Department of Pharmaceutical Science, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, , Yunnan Province, China.

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Autophagy and Immune-Related Diseases Chapter © Target Autophagy as a Novel Therapeutic Strategy in Autoimmune Diseases Chapter © Use our pre-submission checklist Avoid common mistakes on your manuscript. Introduction Autophagy is a basic protective mechanism for cell homeostasis by degrading redundant proteins, lipids, and organelles [ 1 ].

Full size image. Autophagy influences various human diseases via inflammatory pathways Autophagy is related to various diseases, including neurodegeneration, infection, and cancer [ 29 , 30 , 31 ]. Discussion Autophagy was first identified as a key mechanism in cancer development.

Conclusion In summary, this review provided a profound understanding of the relationship between inflammation and autophagy in various human disorders. Availability of data and materials This article has no additional data. References Münz C.

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Furthermore, the disposal of damaged mitochondria helps preventing cardiomyocyte damage and apoptosis Yan et al. Ulk1 phosphorylation of Rab9 at serine is critical for alternative mitophagy and cardioprotection during ischemia Saito et al. Furthermore, the small GTP-binding protein Rheb activates the complex 1 of the mechanistic target of rapamycin mTORC1 and has been identified as a critical regulator of autophagy during cardiac ischemia, in the setting of metabolic disease Sciarretta et al.

Another key factor involved in cardiomyocyte autophagy induction is NADPH oxidase Nox 4, an enzyme that generates ROS during energy stress in the heart, thereby preserving cellular energy and limiting cell death in energy-deprived cardiomyocytes Sciarretta et al. Autophagy during the reperfusion phase is also triggered by oxidative stress, but linked to an upregulation of Beclin 1 and considered detrimental in this condition according to some studies Valentim et al.

In rat cardiomyocytes, the knockdown of Beclin 1 expression by RNA interference inhibited autophagy, while enhancing cell survival Valentim et al. Beclin 1 plays a key role at the interface between autophagy and apoptosis, which are tightly connected cellular processes Kang et al.

The proapoptotic kinase mammalian Stelike kinase-1 Mst-1 acts as a molecular switch that selectively drives autophagy or apoptosis by preferentially altering the formation of Bcl-2—Beclin 1 complexes Maejima et al. In various transgenic mouse models subjected to permanent left anterior descending LAD ligation, Mst1 promoted cardiac dysfunction by inhibiting autophagy, associated with increased levels of Thr -phosphorylated Beclin1.

Mechanistically, activation of Mst-1 in energy-deprived cardiomyocytes resulted in Beclin1 phosphorylation, which enhanced the interaction between Beclin1 and Bcl-2 and Bcl-xL.

Impaired autophagic flux during reperfusion may represent a pathological mechanism contributing to cardiomyocyte death. In support of this, reoxygenation of rat neonatal cardiomyocytes after hypoxia increased cell death compared with hypoxia alone, which was accompanied by markedly increased autophagosomes but not autolysosomes, and impaired clearance of polyglutamine aggregates, indicating a disturbed autophagic flux Ma et al.

This defect was linked to a reduced expression of LAMP2, a critical determinant of autophagosome-lysosome fusion. The resulting autophagosome accumulation was associated with increased ROS and ROS-induced BECLIN1 upregulation, mitochondrial permeabilization, and cardiomyocyte death.

Inhibition of GSK-3β stimulated mTOR signaling and inhibited autophagy through a rapamycin-sensitive mTOR dependent mechanism Zhai et al.

This may provide a mechanistic explanation for the well-established cardioprotective and anti-hypertrophic effects of NPPA in cardiac stress conditions. In summary, the precise cellular survival or cell death pathways in cardiomyocytes seem highly context-dependent.

This might be linked to disturbed autophagosome degradation. The precise mechanisms and conditions that may turn into a detrimental outcome deserve further investigation, in view of potential therapeutic strategies to improve cardioprotective autophagic flux in the acute phase post-MI.

Some preclinical data have indeed shown the beneficial effects of autophagy induction by limiting adverse remodeling in permanent LAD ligation models, e.

Moreover, targeting particular long noncoding RNAs to modulate autophagy has been suggested as a therapeutic strategy in the context of myocardial infarction and heart failure Wang et al. While the previous section focused on the role of autophagy in cardiomyocytes during cardiac ischemic stress and reperfusion injury, it is also important to consider the role of innate immune cells in this context.

Here, we will focus on mechanisms that are relevant for maintaining cardiac homeostasis in steady-state conditions, as well as in post-myocardial infarction inflammation and subsequent repair processes.

To maintain the high cardiac energy demand required for contraction and relaxation, cardiomyocytes contain a large number of mitochondria. The maintenance of a pool of healthy mitochondria is essential for sustaining normal cardiac performance.

Therefore, mitochondrial recycling and quality control are tightly controlled via mitophagy. However, given that cardiomyocytes are subjected to intense mechanical stress and metabolic demands, the question arises of how these postmitotic cells with virtually no turnover are able to preserve cellular homeostasis.

In a recent study, Nicolas-Avila et al. Advanced imaging techniques including light sheet microscopy and confocal microscopy revealed that cardiomyocytes are surrounded by on average five cardiac macrophages and form direct interactions. Cardiomyocytes thereby eject dysfunctional mitochondria and other cargo through an autophagosomal process into particles called exosphers.

The uptake of these exosphers by the surrounding macrophages is mediated by Mertk and prevents extracellular waste accumulation and inflammasome activation, which is crucial for cardiac homeostasis. Ischemic cardiac stress by permanent LAD ligation increased mitochondrial ejection via exosphers.

Another important study highlighted the contribution of autophagy in the maturation and function of neutrophils Riffelmacher et al. Neutrophils play a critical role as one of the first lines of innate immune response to protect the host from exogenous pathogens and to repair the damaged tissue.

Due to their short lifespan, neutrophils are constantly produced in the bone marrow from hematopoietic progenitors in a process named granulopoiesis and released as mature neutrophils into the blood stream Soehnlein et al. Riffelmacher et al. The highest levels of autophagic flux were observed in the early stages of differentiation, as compared to reduced autophagic flux observed at the final maturation stage.

Targeted deletion of Atg7 in neutrophil progenitors resulted in an accumulation of immature neutrophils in the bone marrow.

More detailed metabolic analyses further revealed that neutrophil differentiation was accompanied by a shift towards mitochondrial respiration with the downregulation of glycolysis, which was blunted in autophagy-deficient neutrophils.

Adding exogenous FFAs to Atg7 -deficient neutrophil precursors restored their differentiation, suggesting that the oxidation of FFAs produced by autophagy provides the necessary ATP for neutrophil differentiation.

A different study demonstrated that autophagy is also required for neutrophil degranulation and NADPH-oxidase-mediated reactive oxygen species production Bhattacharya et al.

Myeloid-specific deletion of Atg7 reduced the inflammatory activity of neutrophils in vitro and in a murine model of experimental autoimmune encephalomyelitis. In particular, the relevance of neutrophil-secreted factors including neutrophil gelatinase-associated lipocalin, NGAL in the regulation of macrophage polarization during the post-ischemic myocardial healing phase was demonstrated in an experimental model of permanent infarction Horckmans et al.

A more recent study highlighted the relevance for endothelial autophagy in regulating neutrophil infiltration to sites of inflammation Reglero-Real et al.

Inflamed venular endothelial cells upregulated autophagy selectively at endothelial cell junctions, which was temporally aligned with the peak of neutrophil trafficking. Endothelial cell Atg5 deficiency resulted in excessive neutrophil transendothelial migration and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues.

However, the precise mechanisms of neutrophil extravasation in the ischemic myocardium have not been studied as imaging of leukocyte trafficking in the beating heart remains very challenging Steffens et al. Hence, we may only speculate that the molecular mechanisms determining neutrophil diapedesis in remote areas of the infarcted heart or reperfused infarct zone are comparable to the processes studied in venules of other inflammatory sites.

In addition, there is evidence that autophagy is relevant for monocyte differentiation into macrophages Jacquel et al. While the healthy heart contains a heterogeneous population of tissue-resident macrophages with distinct origins and functions, the macrophage repertoire becomes even more diverse in response to cardiac injury, as blood-borne monocytes migrate into the myocardium and differentiate into macrophages to remove dying tissue, scavenge pathogens and promote healing Swirski and Nahrendorf, ; Zaman and Epelman, Hence, it can be speculated that monocyte autophagic flux is an important process in the immune response to cardiac injury.

However, an experimental study focusing on macrophage lysosomal function in post-myocardial infarction adverse remodeling found that ATG-dependent autophagy was dispensable, at least in this particular experimental model Javaheri et al.

Surprisingly, all these effects were independent of myeloid ATG5 expression. Consequently, pharmacological targeting of autophagy in this condition could represent a possible therapeutic strategy to limit MI-induced cardiac damage, adverse remodeling and heart failure.

Evidence on the contribution of selective autophagy in cardiac pathophysiology is accumulating and extends beyond mitophagy Kirkin et al. A crucial role in selectivity is exerted by adaptor proteins that bind specific cargoes and interact with conjugated LC3 via conserved LIR domains.

The proteins SQSTM1 also known as p62 and Neighbor of BRCA1 gene 1 NBR1 are among the best-characterized examples Gatica et al. Structurally, they own an LIR motif, homo- or hetero-oligomerization domains, and a C-terminal ubiquitin-binding UBA domain binding ubiquitinated cargos.

In clearing misfolded proteins, polyubiquitination of the cargo is essential so that they can bind to SQSTM1, be included in autophagosomes, and then be sent for lysosomal degradation Gatica et al.

The UBA domain interacts with ubiquitin chains attached to the cargo, while the LIR motif interacts with ATG8 family proteins e. SQSTM1 tends to cluster in p62 bodies when its levels are increased. In human cells, p62 bodies are often observed as discrete punctae.

NBR1 serves as a chain terminator of SQSTM1 filaments Jakobi et al. Since shorter SQSTM1 filaments form p62 bodies more easily, NBR1 plays a key role in promoting their assembly by regulating p62 filament length. Furthermore, NBR1 contains multiple domains involved in cargo recruitment, and the interaction between the SQSTM1 and NBR1 allows for more efficient cargo recognition.

Given the strong cooperative activities of NBR1 and SQSTM1, it is often difficult to distinguish the specific effects of each protein. A reduction in SQSTM1 levels, autophagosomes, and p62 bodies correlates with the progression of the autophagic flux toward its late steps. Their amount is inversely related to cellular autophagy levels, decreasing when lysosomal degradation has occurred successfully Katsuragi et al.

Notably, upregulation of SQSTM1 has been observed in most human failing hearts due to ischemic and non-ischemic heart disease Weekes et al. In the example, desmin-related cardiomyopathy is determined by the accumulation of desmin-misfolded aggregates and is characterized by higher expression of SQSTM1 at mRNA and protein levels and SQSTM1 silencing impaired autophagosomal formation, exacerbated cell injury, thus increasing cardiomyocyte death Zheng et al.

Aging is also characterized by the accumulation of protein aggregates. Analysis of human specimens from young 10 years old and aged individuals 65 years old revealed a significantly higher accumulation of SQSTM1 in aged hearts with a direct correlation with age Li C.

et al. Loss of SQSTM1 has been associated with accelerated aging, while overexpression of the SQSTM1 and NBR1 in Drosophila and C.

Elegans increases lifespan suggesting their possible protective role during aging Aparicio et al. In line with a protective role against proteotoxic stress, SQSTM1 is required to increase the autophagic flux in cardiomyocytes with dysfunctional proteasomal degradation of ubiquitinylated proteins, and its genetic deletion aggravated diastolic dysfunction upon pharmacological inhibition of the proteasome Pan et al.

On the other hand, in the context of ischemia-reperfusion, SQSTM1 forms a complex with the necrosome proteins RIP1 and RIP3, and its silencing in vivo protects the aged hearts from necrosis Li C. Similarly, SQSTM1 may scaffold other proteins involved in cell death mechanisms, such as caspases, and is instrumental to the homocysteine-induced apoptosis and autosis an autophagy-dependent cell death of cardiomyocytes Yin et al.

These findings further highlight the complexity of autophagy and its mechanisms in cardiac biology. In conclusion, selective autophagy uses SQSTM1 as critical receptors for cargo selection in cooperation with NBR1 and other adaptors.

Disruptions in their ability to deliver specific cargo for degradation may lead to disruption of cell signaling homeostasis with important implications for several cardiovascular diseases. Under normal conditions, the myocardium has low levels of basal autophagy.

Stress conditions can increase its levels to enhance cell survival, with constitutive autophagy maintaining normal cardiac structure and function, and upregulated autophagy occurring during cardiac disease Rothermel and Hill, ; Gustafsson and Gottlieb, However, in several cardiac diseases, autophagy can be downregulated or hyperactivated, therefore becoming detrimental.

Patients with congestive heart failure Takemura et al. In cardiac hypertrophy Hill and Olson, , autophagy plays a role in the progression of structural remodeling toward heart failure Hein et al.

In heart failure, increased autophagy can cause cardiac dysfunction, with autophagy-induced degeneration leading to cardiac cell death Akazawa et al.

Several treatments have been shown to regulate either inducing or inhibiting cardiac autophagy, including drugs for the treatment of cardiovascular diseases e. There are scant data on the downregulation of autophagy in anthracycline-induced cardiotoxicity Ma et al.

The activating or inhibiting effects of TKI on autophagy largely depend on the cell type Hirschbuhl et al. We were the first to demonstrate that ponatinib, the most cardiotoxic agent amongst all FDA-approved TKIs in the treatment of chronic myeloid leukemia, decreased autophagosome formation as well as LC3-II and p62 expression in cardiomyocytes, indicating a blockage of autophagic flux Madonna et al.

Eur Heart J Suppl abstract in Frontiers in CardioVascular Biomedicine Taken together, these data suggest that autophagy may represent a valuable target for limiting damage in non-ischemic cardiac diseases. However, despite the existence of an intimate connection between autophagy and the heart, only a few selective autophagy activator candidates have been recognized so far, depending on the context of cardiac homeostasis and disease.

Under stress conditions, such as starvation, autophagy is increased in the heart, and FYVE And Coiled-Coil Domain Autophagy Adaptor 1 FYCO1 has been linked to autophagy.

FYCO1 is highly expressed in the heart and its role has recently been investigated in vitro and in vivo under basal and stress conditions Kuhn et al. FYCO1 directly interacts with LC3, Rab7, and phosphatidylinositolphosphate PI3K , key players in autophagy Pankiv et al.

Although FYCO1 knockdown reduces autophagy in isolated rat cardiomyocytes, overexpression of FYCO1 leads to increased autophagic flux in vitro. Since overexpression of FYCO1 prevents cardiac dysfunction in response to biomechanical stress, enhancing autophagic flux by overexpressing FYCO1 could be a promising therapeutic strategy to treat or prevent heart failure Kuhn et al.

In adult mice, cardiac-specific deletion of Atg5 leads to contractile dysfunction, hypertrophy and cardiomyopathy, consistent with the notion that basal autophagy levels in cardiomyocytes are required for cellular proteostasis Nakai et al.

In vitro studies with cardiomyocytes harvested from Atg5 -deficient mice revealed that deficiency of the autophagic gene could cause the accumulation of unwanted proteins and contribute to myocardial disease Pattison and Robbins, In line with these findings, Lamp2 -deficient mice displayed increased autophagic vacuole accumulation and could not degrade proteins, thereby promoting cardiomyopathy Nishino et al.

In the failing heart, autophagy can cause myocardial cell damage via PARP1 Poly ADP ribose polymerase , which promotes autophagy in cardiomyocytes by modulating FoxO3a a member of the FoxO family of transcription factors Schiattarella and Hill, Changes in cardiac autophagy during sepsis have not been clearly defined.

BECLIN1, an early effector of autophagy in mammals, is ubiquitously expressed Liang et al. Autophagy changes in response to sepsis severity, and Beclin 1 plays a key role in the autophagic response of the septic heart in a mouse model of LPS-induced sepsis Sun et al.

Previous preclinical studies evaluating autophagy as a therapeutic approach for sepsis were mainly focused on the mTOR inhibitor rapamycin Hsieh et al. Because mTOR is involved in the regulation of a variety of pathways, rapamycin may cause unwanted toxicity.

In this regard, Sun et al. In Beclin 1 haploinsufficient mice, load-induced increases in autophagy activity were blunted, and pathological remodeling of the left ventricle was moderately diminished. In contrast, in mice engineered for forced overexpression of Beclin 1 in cardiomyocytes MHC-beclin-1 , pressure overload triggered an amplified autophagic response and pathological remodeling of the heart was more severe Sun et al.

In , researchers identified Rubicon as a protein that suppresses autophagy by interacting with the Beclin 1 complex Matsunaga et al. In mouse models, Rubicon deficiency enhances autophagic flux in the heart during LPS-induced sepsis, thereby maintaining cardiac stroke volume but without affecting myocardial inflammatory responses Zi et al.

Thus, targeting Rubicon may be a promising modality of autophagy modulation in various cardiac conditions. Kanamori et al. While cardiac autophagic activity is enhanced in type 1, it is suppressed in type 2 diabetes.

Lysosomes and autophagosomes accumulate within cardiomyocytes of type 1 diabetic mice, whereas abundant lipid droplets and immature autophagosomes were observed in the heart of type 2 diabetic mice Kanamori et al.

Here, resveratrol, an autophagy enhancer, mitigated diastolic dysfunction in the heart of type 2 diabetic mice, whereas it had opposite effects in the hearts of type 1 diabetic mice, suggesting that resveratrol may be a useful therapeutic target in diabetic cardiomyopathy, depending on the diabetic context Kanamori et al.

Similarly, resveratrol had beneficial effects in ischemic heart failure through autophagic activation Kanamori et al. Consistent with the notion that insulin exerts an inhibitory effect on autophagy, our research group recently demonstrated hyperactivation of autophagy associated with left ventricular dysfunction, remodeling, fibrosis, and myocyte apoptosis in a murine model of insulin-deficient diabetic cardiomyopathy Madonna et al.

Here, empagliflozin preserved cardiac dysfunction and remodeling at least in part, through the inhibition of autophagy. This process was mediated by inactivating the autophagy inducer GSK3β, which resulted in increased serum response factor SRF interaction with serum response element SRE and subsequent upregulation of cardiac actin expression.

Our results describe a novel paradigm in which empagliflozin inhibits the hyperactivation of autophagy through the GSK-3β signaling pathway in the context of diabetes. Taken together, these data provide evidence for the maladaptive role of autophagy in cardiovascular disease, suggesting that there is an optimal zone of cardiomyocyte autophagy that may be beneficial and that treatments resulting in levels of autophagy outside higher or lower this therapeutic window are likely to be deleterious Figure 2.

FIGURE 2. Functional relevance of autophagy for cardiac pathophysiology. Constitutive autophagy of cardiomyocytes under basal conditions is a homeostatic mechanism for normal cardiac structure and function.

Autophagic activity is reduced during aging or following exposure to stressors such as chemotherapy drugs owning cardiotoxicity. However, in hearts exposed to hemodynamic overload or ischemia-reperfusion injury, autophagic activity is upregulated at supraphysiological levels, suggesting a contribution to the maladaptive response of the heart that may lead to heart failure.

Compelling evidence revealed the crucial role of autophagy in preserving cardiac health by ruling cardiac homeostasis under baseline conditions and participating in the mechanisms of response to pathological injuries.

While enhancing autophagy activation has shown beneficial outcomes in aging and longevity in animal models, the identification of a proper therapeutic window in diseased conditions and well-tolerated pro-autophagic drugs is an active research area.

Meeting these medical needs will provide novel therapeutics and ultimately improve the outcome of patients with heart disease. DS and SS performed literature research on the general mechanisms of autophagy and involvement in aging and immune response to ischemia, SB and RM performed literature research on mechanisms of autophagy in non-ischemic diseases and therapeutic perspectives.

All the authors contributed in writing the manuscript and made clinical revisions. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission.

Neither the European Union nor the European Commission can be held responsible for them. Abdellatif, M. Fine-tuning cardiac insulin-like growth factor 1 receptor signaling to promote health and longevity.

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Henderson, J. LpSpl with sphingosine-1 phosphate lyase activity reduces sphingolipid levels, reducing -autophagosome formation. Legionella pneumophila is a common pulmonary pathogen infecting human lung alveolar macrophages and causing pneumonia [ 59 ].

It evades the immune response by residing in a special vacuole formed from the endoplasmic reticulum membrane and by inhibiting ly-sosome fusion [ 60, 61 ]. Autophagy was shown to be critical for L. pneumophila elimination in an in vitro study showing that knockdown of Atg5 in mouse macrophages enhanced bacterial replication [ 62 ].

Furthermore, in vivo studies using the Atg9 mutant Dictyostelium discoideum showed a critical defect in the clearance of L. Legionella developed strategies to counter cellular autophagy elimination.

Another effector protein, LpSpl, acts as sphingosine-1 phosphate lyase, decreasing host cell sphingolipid levels to inhibit autophagosome formation Fig.

A common pulmonary virus pathogen, Influenza virus A, induces autophagy but blocks the auto-phagosome-lysosome fusion by the viral Matrix 2 M2 ion-channel protein [ 66 ]; thus, the virus adapts the multifunctional autophagosomes to reproduce the virus components and replicate Fig.

Consistent with the role of autophagy in host defense, recent studies have addressed the augmentation of autophagy as a method to enhance the clearance of pathogens including Pseudomonas aeruginosa [ 68 ] and Burkholderia cenocepacia [ 69 ].

Recent studies have found that autophagy is a negative regulator of inflammation in general, and of NLRP3 inflammasome in particular. The inflammasome is a multiprotein complex responsible for caspase-1 activation.

Activation of caspase-1 leads to the release of the active form of potent inflammatory cytokines, including IL-1β and IL, by proteolytic cleavage. Macrophages from -Atg16L1-deficient mice produced exaggerated quantities of IL-1β and IL in response to LPS [ 70 ].

Depletion of other autophagic proteins such as Atg7, LC3B, or Beclin 1, or treatment with autophagy inhibitors wortmannin or 3-methyladenine, enhanced the production of IL-1β and IL by macrophages [ 70, 71 ].

These studies indicated that autophagy deficiency is associated with increased inflammasome activity. Furthermore, autophagy deficiency in myeloid-derived cells was shown to cause spontaneous pulmonary inflammation in two independent studies [ 72, 73 ]. In both of these studies, mice lacking either Atg5 or Atg7 in myeloid cells spontaneously developed lung inflammation characterized by enhanced recruitment of inflammatory cells into the lung, increased levels of pro-inflammatory cytokines, submucosal thickening, goblet cell metaplasia, and increased collagen content [ 72, 73 ].

Following LPS challenge, these autophagy-deficient mice had higher levels of pro-inflammatory cytokines in serum and in bronchoalveolar lavage, severe pulmonary inflammation, as well as increased mortality compared to wild-type mice [ 72, 73 ].

In addition, mice lacking Atg5 or Atg7 in myeloid cells were more susceptible to bleomycin and silica challenge [ 74 ]. Spontaneous lung inflammation was also found in mice with Atg5 deletion in dendritic cells [ 75 ].

Knockout of other autophagy-related genes such as Atg14, Fip, or Epg5 in myeloid cells led to sterile lung inflammation, thus confirming the essential role of autophagy in lung homeostasis, which is not specific to a particular autophagy-related gene [ 76 ].

During active infection, autophagy also functions to prevent extensive inflammation [ 56, 76, 77 ]. In vivo studies of M. tuberculosis infection showed that, compared to wild-type, mice with myeloid cell-specific Atg5 knockout had a higher bacterial burden, severe necrotic lung lesions, elevated levels of IL and IL-1α, and higher mortality.

These studies suggest that in addition to suppressing M. tuberculosis growth, autophagy in myeloid-derived cells is responsible for controlling damaging inflammation [ 56, 77 ].

A recent study showed that the loss of Atg5 in polymorphonuclear cells causes excessive inflammation and predisposes to M. tuberculosis infection. This study suggested that the role of Atg5 in M.

tuberculosis inhibition could be at least partially independent of autophagy [ 78 ]. The innate immune system is an important component that acts as an initial barrier to protect against microbial pathogens or damaging agents. Cross-talk between autophagy and the innate immune system balances protection of the host against an exaggerated immune response, while enabling the neutralization of infectious and damaging threats.

This is crucial at sites such as the lung, skin, and colon, where the host is continuously exposed to potential hazardous elements, such as inhaled toxins, toxic food products, as well as chemicals and commensal and pathogenic bacteria.

The innate immune system is able to recognize and orchestrate a protective inflammatory response against harmful insults. Such responses should be tightly controlled to prevent exaggerated damage to the host.

The innate immune system relies on a group of pattern-recognition receptors that include toll-like receptors TLRs , nucleotide-binding oligomerization domain-like receptors NLRs , and absent in melanoma AIM2 -like receptors ALRs.

Both NLRs and ALRs can form a cytoplasmic multiprotein complex called the inflammasome upon sensing a wide variety of ligands. Inflammasome assembly involves the adapter protein apoptosis-associated speck-like protein containing a caspase-recruitment domain ASC which recruits caspase Activation of caspase-1 leads to the release of the active form of IL-1β and IL by proteolytic cleavage and can also lead to a form of cell death called pyroptosis [ 79 ].

The most widely studied inflammasome is NLRP3. Its activation depends on two steps. In the first step, pathogen-associated molecular patterns PAMPs and damage-associated molecular patterns DAMPs are recognized by TLRs to activate NF-κB signaling-dependent expression of the inflammasome components and pro-cytokines Fig.

In the second step, specific stimuli trigger inflammasome complex assembly and the inflammasome processes the pro-cytokine to generate mature cytokines by active caspases Fig. A recent study revealed that newly synthesized mitochondrial DNA may act as an NLRP3 ligand and directly associate with the NLRP3 inflammasome complex, thereby promoting its activity [ 80 ].

There have been several mechanisms proposed for how autophagy deficiency can lead to inflammasome activation. Autophagy has also been suggested to suppress inflammasome activation by directly digesting inflammasome components such as ubiquitinated ASC Fig.

Furthermore, autophagy was found to directly sequester pro-cytokines such as pro-IL-1β for digestion to reduce mature cytokine production Fig. Mice with Atg7 deficiency in myeloid cells developed spontaneous lung inflammation that was mostly mediated by IL Neutralization of IL, but not IL-1β or IL, attenuated lung inflammation in these mice.

In contrast, increased mortality in response to endotoxin was caused by increased IL-1β [ 62 ]. In addition to the effect of autophagy on inflammasome-associated cytokines, several studies have suggested an effect of autophagy or auto-phagic proteins on cytokines that are not associated with inflammasome activation.

In mice, Atg5-deficient macrophages produced more pro-inflammatory cytokine IL-1α in an inflammasome-independent way [ 77 ].

In Influenza A virus infection, excessive immune responses, including increased neutrophil and macrophage infiltration, contribute to lung injury and pathology more than the effects of viral replication [ 86 ].

Autophagy in host defense and inflammasome regulation. a PAMPs or DAMPs, recognized by pattern-recognition receptors, result in NF-κB activation. Active NK-κB promotes inflammasome components and cytokine expression.

b PAMPs or DAMPs cause mitochondrial damage and the release of mitochondrial ROS and DNA, triggering the assembling of NLRP3, ASC, and Pro-caspase into active inflammasome.

Caspase-1 is activated by autocleavage and then cleaves the pro-inflammatory cytokines IL-1β into active cytokines. Bacteria-containing phagosome membrane disruption leads to the release of PAMPs.

c Activated auto-phagosomes can engulf damaged mitochondria, NLRP3, ASC, and Pro-caspase, and target them to lysosomal degradation, reducing the production and secretion of active cytokines.

Autophagy is an important intracellular recycling system with diverse functions implicated in multiple cellular signaling pathways. Autophagy is regulated at the transcriptional, translational, and posttranslational levels. Phosphorylation and de-phosphorylation on some key proteins in the initiation complexes has been found to be a major mechanism of autophagy regulation [ 18 ].

Recent studies revealed that acetylation could modify autophagy proteins and influence the autophagy cascade [ 21 ]. Further elucidation of these regulatory mechanisms could provide potential therapeutic targets in diseases in which autophagy modulation is desired.

During host infection, autophagy eliminates pathogens by mediating pathogen autolysosomal killing and facilitating antimicrobial antigen presentation [ 5, 77, 87 ]. In addition to pathogen elimination, autophagy tames the host inflammatory response by negative regulation of inflammasome activity.

Multiple studies have shown that the induction of autophagy can have beneficial effects in combating infections, suggesting that promoting autophagy may be a beneficial strategy to control lung infection [ 43, 44 ].

However, some pathogens have evolved adaptive strategies to resist autophagy elimination, potentially limiting the impact of autophagy in immune defense. tuberculosis [ 57 ], RavZ and LpSpl from L. pneumophila [ 64, 65 ], and M2 ion-channel protein from Influenza A [ 67 ] Fig.

These virulence factors contribute to the drug resistance of those pathogens by enhancing pathogen survival in spite of host autophagy. Thus, developing drugs that inactivate pathogen virulence factors involved in autophagy avoidance may represent the next generation of -anti-microbial agents.

We thank Anindita Ravindran, Elmoataz Abdel Fattah, and Li-Yuan Yu-Lee for critical review of the manuscript. Sign In or Create an Account. Search Dropdown Menu.

header search search input Search input auto suggest. filter your search All Content All Journals Journal of Innate Immunity. Advanced Search. Skip Nav Destination Close navigation menu Article navigation. Volume 12, Issue 1. Autophagy in Regulatory and Signaling Pathways.

Cellular Regulation of Autophagy. Autophagy Regulation. Autophagy and the Elimination of Pulmonary Pathogens. Autophagy and Lung Inflammation. Autophagy Regulates Inflammasome Activity. Conclusion and Future Prospects. Statement of Ethics. Disclosure Statement.

Article Navigation. Review Articles April 24 Autophagy in Pulmonary Innate Immunity Subject Area: Further Areas , Immunology and Allergy , Pathology and Cell Biology. Lang Rao ; Lang Rao. Moreover, many studies have demonstrated that various pro-inflammatory cytokines participate in PD pathogenesis, such as TNF-α, IL-4, IL-6, IL, and IL-1β [ 70 ].

Several factors, such as a-synuclein, can serve as DAMPs to recognize PRRs, and leucine-rich repeat kinase 2 LRRK2 from the RIPK family and are involved in autophagy induction. Exogenous overexpression of a-synuclein leads to lysosomal damage and autophagy, which can be stimulated by tau protein related to Alzheimer's disease [ 71 ].

Exceptionally compelling is the framework comprising E3 ubiquitin ligase PRKN and PINK1 fit for driving mitophagy. However, in animal models, PINK1 and PRKN are not associated with PD.

Additionally, transformations might enhance α-synuclein levels and induce familial PD. Although autophagy is reversed by A53T overexpression, the overabundance of intracellular α-synuclein disables autophagy by restraining the small GTPase Rab-1A.

Finally, increased α-synuclein expression can induce protein accumulation and diminish autophagy, decreasing mitophagy and increasing neuronal apoptosis. Two classical AD hallmarks are the accumulation of p-tau protein and the deposition of Aβ plaques [ 73 ]. These perceptions proposed that imperfections in autophagic development might be an overall element of AD pathology.

For example, in AD, autophagy might be weakened by autophagosome corruption and autophagosome formation, albeit those effects might fluctuate according to genotype and diseased phase. Hereditary examinations have also demonstrated a few transformations that induce intriguing familial AD types, such as the mutation of amyloid antecedent protein APP , presenilin-1, and presenilin-1—1 PS 1 and 2 [ 75 , 76 ].

Also, autophagy might be downregulated during autophagosome development in AD patients. Compared to healthy individuals, AD patients show diminished Beclin-1 articulation, which might prompt disability in autophagic movement.

Beclin-1 heterozygous knockout in mice that express the AD-related human APP leads to APP and Aβ accumulation and displays more extreme neurodegeneration contrasted with Beclin-1 WT mice.

Additionally, pathogenic APP and tau are corrupted via autophagy. Consistently, 3-MA, a specific autophagy inhibitor, increments tau harmfulness, while rapamycin autophagy inducer diminishes tau effects in the cell [ 77 ]. Nonetheless, a previous review has shown that 3-MA or Beclin-1 knockdown could reduce Aβ disposition in neuroblastoma and glioma cells [ 78 ].

The discussion on the cytoprotective versus cytotoxic roles of autophagy in AD models might be clarified by assessing the autophagic motion and the level of lysosomal imperfection for each situation.

Further examinations are expected to expand the role of autophagy in AD. Autophagy was first identified as a key mechanism in cancer development. A cancer-suppressive role for autophagy corroborates this. Interestingly, this idea has been challenged by some that propose that autophagy can support oncogenesis because it can assist growth cell endurance [ 79 ].

A growth silencer engaged with the upstream restraint of mammalian target of rapamycin mTOR flagging PTEN, TSC1, and TSC2 turns autophagy on while mTOR activates oncogenes. For example, class I PI3K and Akt switch it off [ 80 ]. Besides, p53 and Death-associated protein kinase DAPK are associated with human malignant growth and control autophagy [ 81 ].

The cell oncogenes Bcl-2 and Bcl-XL are frequently upregulated in human diseases and repress autophagy by inhibiting Beclin Besides, p62 overexpression via autophagy-lysosome promotes carcinogenesis via NF-κB flagging liberation, activating nuclear factor E2-related factor Nrf-2 , inducing ROS production, and leading to DNA damage.

The contrast between these paradoxical features of autophagy makes the association with disease treatment more complex.

Notwithstanding, it has been recommended that in the initial phases of malignant growth, quality control via autophagy, especially over genome upkeep, suppresses carcinogenesis. Autophagy might organize the support or passage of cells into the G0 stage and subsequently forestall the unconstrained proliferation of tumor cells.

Conversely, autophagy might provide nutrition for cancer cells and assist their growth when suffering from metabolic pressure and oppose passing set off by chemotherapeutics [ 82 ].

Furthermore, autophagy promotes growth cell endurance in normal and cancer cells. Although autophagy can postpone apoptosis, cell passing ultimately restricts autophagy. Apoptosis ordinarily escapes growing cells, granting supported endurance, movement, and protection from treatment.

The delayed pressure endurance managed by imperfect apoptosis occurs in cancer cells by either increased anti-apoptotic genes Bcl-2 and Bcl-xL or deficiency in pro-apoptotic genes Bax and Bak [ 83 ]. The shortfall of cell passing is insufficient to support the pressure endurance of growing cells.

Thus, the pressure from glucose oxygen deprivation strongly enacts autophagy, upholding apoptotic cells' long-term endurance. Cancer cells evading apoptosis can also obtain nutrition via autophagy when they endure pressure for a long time and enter a torpid condition.

They can leave torpidity to continue cell multiplication when the pressure is released and typical development conditions are reestablished [ 84 ]. Hereditary or pharmacologic concealment of autophagy advances cell demise by putrefaction in vitro and in vivo, which suggests that growing and quiescent cells use autophagy to keep up with endurance in distressing conditions [ 85 ].

Autophagy limits these hypoxic districts, where it upholds growing cell endurance. Oxygen-detecting hypoxia-inducible factors activate autophagy alongside other metabolic factors and favor angiogenesis pathways unaffected by cell variation to metabolic pressure.

Autophagy induction in hypoxic areas might also hamper treatment due to proliferative cells that are resistant to treatment in these hypoxic areas. Hence, determining the cancer cell torpidity and recovery component and how to target this pathway to build novel anti-cancer strategies is essential.

Currently, lysosomotropism specialists e. On the other hand, autophagy can also effectively exhibit antitumor activity in some contexts, especially in focused growth cells or when blended with restorative mTOR hindrance. In this case, autophagy might improve endurance, conceivably subverting treatment.

Besides, various strategies using 3-MA, chloroquine, or hereditary manipulation of autophagy-related genes have shown that autophagy hindrance might sharpen growing cells to death, acting on assorted cytotoxic specialists [ 87 ].

Moreover, proteasome inhibitors can effectively trigger autophagy. Mechanistically, proteins can be degraded via two classical pathways: autophagy—lysosomal and ubiquitin—proteasome pathways. Inhibiting the ubiquitin—proteasome pathway activates the autophagy—lysosomal pathway.

For example, Bortezomib an FDA-approved proteasome inhibitor effectively enhances autophagy in colorectal cancer and myeloma cells [ 89 , 90 ]. Consistently, proteasome hindrance in prostate malignant growing cells by NPI can act through autophagy by an eIF2α-subordinate component that controls ATG function [ 91 ].

The concurrent inhibition of the two systems can result in a more effective strategy against cancer cells than the restraint of either pathway alone, which should be tested in the future. In summary, this review provided a profound understanding of the relationship between inflammation and autophagy in various human disorders.

Autophagy can assume fundamental roles in inflammatory diseases, infections, and carcinogenesis. A better comprehension of autophagy in different diseases has promising effects on developing improved treatments. Meanwhile, autophagy studies are still being conducted, although their relevance to digestion, stress reaction, and cell demise pathways is recognized.

Consequently, this cycle and their related reactions might provide data on how the host reacts to exogenous microorganisms and endogenous particles created under pressure conditions, yet these occasions can be re-molded by different stimuli and cell types. Altogether, understanding how autophagy is regulated and directed, and the particularity related to cell utilization, requires further examination.

It will be essential to characterize and portray sub-atomic and biochemical features associated with the intricate exchange among autophagy and different pathologies to advance novel approaches for patients with neurodegenerative diseases and infections.

The field of autophagy in immunity and inflammation-related diseases continues to evolve in both fundamental and translational fields.

In general, almost all human diseases possess an inflammatory component, which in turn provides a window of opportunity and a challenge to develop autophagy-based therapeutic strategies. Considering the irreplaceable role of autophagy in the removal of the primary toxic entity causing disease and subsequently reducing the susceptibility to pro-death insults, which implying autophagy is a promising target mechanism from a therapeutic perspective.

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In addition, autophagy is involved in various aspects of immunity, including the clearance of pathogens, cytokines, and immune signals, suggesting that autophagy also plays important roles in innate [ 3, 4 ] and adaptive immunity [ 5 ].

The canonical autophagy pathway can be separated into three major steps: initiation, elongation, and maturation [ 6 ]. Each step is regulated by specific autophagy-related Atg proteins [ ]. In the initiation step, with the activation of the ULK1 kinase complex, a small membranous sac called a phagophore is formed.

A second kinase complex called the Vps34 complex is then recruited to the phagophore membrane [ 6 ]. Vps34 catalyzes the phosphorylation of cellular phosphatidylinositol to produce phosphatidylinositol 3-phosphate PI3P , which serves as a platform to recruit more Atg proteins to promote the elongation of autophagic membranes Fig.

In the elongation step, two ubiquitin-like conjugation systems, Atg12—Atg5-Atg16L and LC3—PE, are involved. In the first ubiquitin-like system, Atg12 acts as a ubiquitin-like protein and, with the help of Atg7 and Atg10, becomes conjugated to Atg5.

The resulting complex subsequently interacts with the coiled-coil protein Atg16L1 to form the Atg12—Atg5-Atg16L complex [ 10 ]. In the second ubiquitin-like system, pro-LC3 is cleaved by the cysteine protease Atg4, exposing a C-terminal glycine residue [ 11 ].

LC3 is then transiently linked to Atg7 and Atg3, and is eventually conjugated to phosphatidylethanolamine to form the mature form of lipid protein LC3II. The two systems work together to expand phagophore membrane formation that leads to mature autophagosomes Fig.

The mature autophagosomes then fuse with lysosomes to create autolysosomes and the acidic proteolytic environment of the autolysosome contributes to the degradation of the inner membrane as well as the luminal contents inside the autophagic vacuoles [ 6, 9 ]. Simplified autophagy signaling pathway and regulation.

a Nutrition deprivation inhibits mTOR, which in turn activates ULK1 complex. Energy deprivation is sensed by AMPK to suppress mTOR and activates ULK1 complex.

Activated ULK1 complex recruits VpsBeclin-1 complex to produce PI3P and initiates phagosome formation. b Two conjugation systems, Atg12—Atg5-Atg16L and LC3—PE, facilitate phagophore membrane elongation and autophagosome maturation. c NAD-dependent deacetylase Sirt1 catalyzes deacetylation of Vps34, Beclin1, Atg5, Atg7, and LC3 to promote autophagy.

d Transcription factors TFEB and FoxO translocate to the nuclear to induce autophagy-related gene expression. Their transcription activity can be inhibited by phosphorylation caused by mTOR or AKT, respectively.

Phosphorylated TFEB is digested by proteasome; ZKSCAN3 repress autophagy-related gene transcription. Autophagosomes can be processed in the absence of some key autophagy components, in a process described as noncanonical autophagy [ 12, 13 ].

Non-canonical autophagy can also be processed without the ubiquitin conjugation proteins Atg5 and Atg7 [ 14, 15 ], and this type of autophagy has been found to play an important role in mitochondrial digestion during erythroid maturation in vivo [ ].

LC3-associated phagocytosis LAP is a distinct form of noncanonical autophagy. It engages most of the canonical autophagy components, such as the Class III PI3K complex and ubiquitinylation-like protein-conjugation systems [ 17 ]. However, LAP proceeds without the ULK1 complex to form LC3-conjugated single-membraned phagosomes [ 17 ].

While the autophagy cascade could be affected in all three steps of the pathway, most regulation of autophagy occurs at the initiation step [ 9, 18 ]. mTOR acts as a cellular nutritional sensor, phosphorylating ULK1, thus inhibiting autophagy initiation in nutrient-sufficient conditions [ 9, 18 ].

Under starvation or treatment with mTOR inhibitors such as rapamycin, mTOR activity is inhibited and ULK1 is rapidly dephosphorylated, resulting in activation of the ULK1 kinase Fig. AMPK activates autophagy initiation through inhibiting mTORC1 and activating the ULK1 complex Fig.

Vps34 kinase activity depends on VpsBeclin1 interaction as the direct downstream target of ULK, and it is inhibited by kinase inhibitor 3-methyladenine 3-MA and wortmannin [ 18 ].

A recent study showed that the activity of Vps34 is also inhibited by acetyltransferase p [ 19 ]. Autophagy can be regulated at the transcriptional level. Forkhead transcription factors FoxOs upregulate autophagy by promoting the transcription of Atg genes, including Atg4, LC3B, and ULK1 [ 23, 24 ].

The activity of FoxOs depends on its nuclear localization. Transcription factor EB TFEB is another newly identified master transcription regulator of autophagy [ 25, 26 ]. Like FoxOs, the activation of TFEB is also dependent on nuclear translocation of the non-phosphorylated form of TFEB.

mTOR and MAPK are extracellular signaling kinases that catalyze TFEB phosphorylation and restrain its nuclear translocation, inhibiting its activity Fig. Our studies show that TFEB activity could also be regulated by proteasome-mediated degradation of phosphorylated TFEB [ 29, 30 ].

In contrast to FoxOs and TFEB, the transcriptional factor ZKSCAN3, which controls cell proliferation [ 31 ], has recently been identified to act as a repressor to a wide range of Atg genes. Knockdown of ZKSCAN3 has been shown to induce autophagy and lysosome biogenesis Fig. In addition to its role in maintaining cellular homeostasis, autophagy is actively engaged in cellular host defense by reducing the pathogen burden [ 33 ].

Mycobacterium tuberculosis bacteriumis a notorious pulmonary pathogen. tuberculosis primarily infects alveolar phagocytic cells, in which it resides and multiplies within the host-derived phagosomes [ 34 ].

tuberculosis developed strategies to escape phagocytotic clearance by preventing phagosome-lysosome fusion [ 35 ], disrupting vacuolar H-ATPase recruitment and phagosome acidification [ 36, 37 ], and inhibiting PI3P-dependent membrane trafficking [ 38, 39 ].

tuberculosis suppress the apoptosis of infected macrophages and trigger necrosis that results in the spreading of more bacteria to infect adjacent cells [ 40, 41 ].

Multiple studies have shown that autophagy plays an important role in innate defense against M. tuberculosis infection [ ]. Stimulation of autophagy by starvation, rapamycin, IFN-γ [ 4 ], ATP [ 46 ], or lipopolysaccharides LPS [ 44, 47 ] promoted the transfer of intracellular mycobacteria to lysosomes to be killed.

Furthermore, vitamin D, which was used to treat tuberculosis in the preantibiotic era, has been shown to exert anti- M. tuberculosis effects by stimulating autophagy through induction of the antibacterial peptide, cathelicidin [ ]. Antituberculosis drugs such as isoniazid and pyrazinamide have been shown to be partly dependent on autophagy activation, because in autophagy-defective cells antibiotic treatment was less effective against mycobacteria [ 51 ].

Additionally, autophagy deficiency also indirectly affects M. tuberculosis infection by enhancing macrophage uptake of mycobacteria through upregulation of scavenger receptor expression [ 52 ] and inhibiting antigen presentation [ 5, 47 ]. Some M. tuberculosis virulence factors facilitate intracellular bacterial survival by autophagy inhibition.

Recent evidence indicates that SapM blocks -autophagosome-lysosome fusing by binding with GAPase RAB7 [ 53 ]. ManLAM was also found to suppress auto-phagosome formation [ 54 ]. Another mycobacterial secreted protein is Eis, which is an N-acetyltransferase that enhances the survival of mycobacteria in human monocytic cells.

It suppresses autophagy by acetylating JNK-specific phosphatase MKP-7 to inhibit JNK-dependent autophagy efflux initiation [ 55 ]. The M. tuberculosis ESX-1 secretion system [ 56 ] was found to inhibit autophagic flux by blocking autophagosome-lysosome fusion in human dendritic cells [ 57 ].

A recent study of M. Strategies used by pulmonary pathogens to avoid host autophagy. tuberculosis has five identified anti-autophagy factors.

Eis is an N-acetyltransferase. It acetylates JNK-specific phosphatase MKP-7 to initiate the inhibition of JNK-dependent autophagy. Mannose-capped lipoarabinomannan ManLAM interferes with trafficking proteins in autophagy and also affects LC3 protein expression levels and inhibits accumulation of autophagic vacuoles.

b RavZ, the bacterial effector protein of L. pneumophila , inhibits autophagy by hydrolyzing the release of LC3II phosphatidylethanolamine at the carboxyl-terminal glycine residue. The hydrolyzed LC3 cannot be reconjugated by Atg7 and Atg3 to form mature LC3II for autophagosome localization.

LpSpl with sphingosine-1 phosphate lyase activity reduces sphingolipid levels, reducing -autophagosome formation. Legionella pneumophila is a common pulmonary pathogen infecting human lung alveolar macrophages and causing pneumonia [ 59 ]. It evades the immune response by residing in a special vacuole formed from the endoplasmic reticulum membrane and by inhibiting ly-sosome fusion [ 60, 61 ].

Autophagy was shown to be critical for L. pneumophila elimination in an in vitro study showing that knockdown of Atg5 in mouse macrophages enhanced bacterial replication [ 62 ].

Furthermore, in vivo studies using the Atg9 mutant Dictyostelium discoideum showed a critical defect in the clearance of L.

Legionella developed strategies to counter cellular autophagy elimination. Another effector protein, LpSpl, acts as sphingosine-1 phosphate lyase, decreasing host cell sphingolipid levels to inhibit autophagosome formation Fig.

A common pulmonary virus pathogen, Influenza virus A, induces autophagy but blocks the auto-phagosome-lysosome fusion by the viral Matrix 2 M2 ion-channel protein [ 66 ]; thus, the virus adapts the multifunctional autophagosomes to reproduce the virus components and replicate Fig.

Consistent with the role of autophagy in host defense, recent studies have addressed the augmentation of autophagy as a method to enhance the clearance of pathogens including Pseudomonas aeruginosa [ 68 ] and Burkholderia cenocepacia [ 69 ].

Recent studies have found that autophagy is a negative regulator of inflammation in general, and of NLRP3 inflammasome in particular. The inflammasome is a multiprotein complex responsible for caspase-1 activation. Activation of caspase-1 leads to the release of the active form of potent inflammatory cytokines, including IL-1β and IL, by proteolytic cleavage.

Macrophages from -Atg16L1-deficient mice produced exaggerated quantities of IL-1β and IL in response to LPS [ 70 ]. Depletion of other autophagic proteins such as Atg7, LC3B, or Beclin 1, or treatment with autophagy inhibitors wortmannin or 3-methyladenine, enhanced the production of IL-1β and IL by macrophages [ 70, 71 ].

These studies indicated that autophagy deficiency is associated with increased inflammasome activity. Furthermore, autophagy deficiency in myeloid-derived cells was shown to cause spontaneous pulmonary inflammation in two independent studies [ 72, 73 ].

In both of these studies, mice lacking either Atg5 or Atg7 in myeloid cells spontaneously developed lung inflammation characterized by enhanced recruitment of inflammatory cells into the lung, increased levels of pro-inflammatory cytokines, submucosal thickening, goblet cell metaplasia, and increased collagen content [ 72, 73 ].

Following LPS challenge, these autophagy-deficient mice had higher levels of pro-inflammatory cytokines in serum and in bronchoalveolar lavage, severe pulmonary inflammation, as well as increased mortality compared to wild-type mice [ 72, 73 ].

In addition, mice lacking Atg5 or Atg7 in myeloid cells were more susceptible to bleomycin and silica challenge [ 74 ]. Spontaneous lung inflammation was also found in mice with Atg5 deletion in dendritic cells [ 75 ].

Knockout of other autophagy-related genes such as Atg14, Fip, or Epg5 in myeloid cells led to sterile lung inflammation, thus confirming the essential role of autophagy in lung homeostasis, which is not specific to a particular autophagy-related gene [ 76 ].

During active infection, autophagy also functions to prevent extensive inflammation [ 56, 76, 77 ]. In vivo studies of M. tuberculosis infection showed that, compared to wild-type, mice with myeloid cell-specific Atg5 knockout had a higher bacterial burden, severe necrotic lung lesions, elevated levels of IL and IL-1α, and higher mortality.

These studies suggest that in addition to suppressing M. tuberculosis growth, autophagy in myeloid-derived cells is responsible for controlling damaging inflammation [ 56, 77 ]. A recent study showed that the loss of Atg5 in polymorphonuclear cells causes excessive inflammation and predisposes to M.

tuberculosis infection. This study suggested that the role of Atg5 in M. tuberculosis inhibition could be at least partially independent of autophagy [ 78 ]. The innate immune system is an important component that acts as an initial barrier to protect against microbial pathogens or damaging agents.

Cross-talk between autophagy and the innate immune system balances protection of the host against an exaggerated immune response, while enabling the neutralization of infectious and damaging threats. This is crucial at sites such as the lung, skin, and colon, where the host is continuously exposed to potential hazardous elements, such as inhaled toxins, toxic food products, as well as chemicals and commensal and pathogenic bacteria.

The innate immune system is able to recognize and orchestrate a protective inflammatory response against harmful insults. Such responses should be tightly controlled to prevent exaggerated damage to the host. The innate immune system relies on a group of pattern-recognition receptors that include toll-like receptors TLRs , nucleotide-binding oligomerization domain-like receptors NLRs , and absent in melanoma AIM2 -like receptors ALRs.

Both NLRs and ALRs can form a cytoplasmic multiprotein complex called the inflammasome upon sensing a wide variety of ligands. Inflammasome assembly involves the adapter protein apoptosis-associated speck-like protein containing a caspase-recruitment domain ASC which recruits caspase Activation of caspase-1 leads to the release of the active form of IL-1β and IL by proteolytic cleavage and can also lead to a form of cell death called pyroptosis [ 79 ].

The most widely studied inflammasome is NLRP3. Its activation depends on two steps. In the first step, pathogen-associated molecular patterns PAMPs and damage-associated molecular patterns DAMPs are recognized by TLRs to activate NF-κB signaling-dependent expression of the inflammasome components and pro-cytokines Fig.

In the second step, specific stimuli trigger inflammasome complex assembly and the inflammasome processes the pro-cytokine to generate mature cytokines by active caspases Fig.

A recent study revealed that newly synthesized mitochondrial DNA may act as an NLRP3 ligand and directly associate with the NLRP3 inflammasome complex, thereby promoting its activity [ 80 ]. There have been several mechanisms proposed for how autophagy deficiency can lead to inflammasome activation.

Autophagy has also been suggested to suppress inflammasome activation by directly digesting inflammasome components such as ubiquitinated ASC Fig.

Furthermore, autophagy was found to directly sequester pro-cytokines such as pro-IL-1β for digestion to reduce mature cytokine production Fig.

Mice with Atg7 deficiency in myeloid cells developed spontaneous lung inflammation that was mostly mediated by IL Neutralization of IL, but not IL-1β or IL, attenuated lung inflammation in these mice.

In contrast, increased mortality in response to endotoxin was caused by increased IL-1β [ 62 ]. In addition to the effect of autophagy on inflammasome-associated cytokines, several studies have suggested an effect of autophagy or auto-phagic proteins on cytokines that are not associated with inflammasome activation.

In mice, Atg5-deficient macrophages produced more pro-inflammatory cytokine IL-1α in an inflammasome-independent way [ 77 ]. In Influenza A virus infection, excessive immune responses, including increased neutrophil and macrophage infiltration, contribute to lung injury and pathology more than the effects of viral replication [ 86 ].

Autophagy in host defense and inflammasome regulation. a PAMPs or DAMPs, recognized by pattern-recognition receptors, result in NF-κB activation. Active NK-κB promotes inflammasome components and cytokine expression. b PAMPs or DAMPs cause mitochondrial damage and the release of mitochondrial ROS and DNA, triggering the assembling of NLRP3, ASC, and Pro-caspase into active inflammasome.

Caspase-1 is activated by autocleavage and then cleaves the pro-inflammatory cytokines IL-1β into active cytokines. Bacteria-containing phagosome membrane disruption leads to the release of PAMPs.

c Activated auto-phagosomes can engulf damaged mitochondria, NLRP3, ASC, and Pro-caspase, and target them to lysosomal degradation, reducing the production and secretion of active cytokines. Autophagy is an important intracellular recycling system with diverse functions implicated in multiple cellular signaling pathways.

Autophagy is regulated at the transcriptional, translational, and posttranslational levels. Phosphorylation and de-phosphorylation on some key proteins in the initiation complexes has been found to be a major mechanism of autophagy regulation [ 18 ].

Recent studies revealed that acetylation could modify autophagy proteins and influence the autophagy cascade [ 21 ]. Further elucidation of these regulatory mechanisms could provide potential therapeutic targets in diseases in which autophagy modulation is desired. During host infection, autophagy eliminates pathogens by mediating pathogen autolysosomal killing and facilitating antimicrobial antigen presentation [ 5, 77, 87 ].

In addition to pathogen elimination, autophagy tames the host inflammatory response by negative regulation of inflammasome activity. Multiple studies have shown that the induction of autophagy can have beneficial effects in combating infections, suggesting that promoting autophagy may be a beneficial strategy to control lung infection [ 43, 44 ].

However, some pathogens have evolved adaptive strategies to resist autophagy elimination, potentially limiting the impact of autophagy in immune defense. tuberculosis [ 57 ], RavZ and LpSpl from L. ATG7- and ATG3-deficient T cells display phenotypes similar to that of ATG5-deficient T lymphocytes, characterized by increased cell death and the defective homeostasis of organelles such as mitochondria and ER Jia and He, The deletion of gene ATG16L1 in mouse macrophages alters the production of IL-1β, which affects the derivation of naïve T cells into Th17 Kaser and Blumberg, Antigen presentation.

Antigenic peptides generated from autophagic degradation can be presented by MHC class II molecules. tuberculosis can escape the immune defense of host cells. In HIV-1 target cells, both canonical autophagy and noncanonical autophagy are involved in the presentation of virus-derived antigens.

HIV-1 specifically encodes Tat, Nef, and Vpu proteins, which perturb the autophagy mechanism and evade the antiviral responses Leymarie et al. The development of B cells.

The maintenance of the B-1a B cell number needs the adequate expression of ATG5 during efficient B cell development. While ATG5 is deleted in B lymphocytes, there is a dramatic decline in the number of B-1 B cells Miller et al. A knockout mouse with conditional deficiency of ATG5 in B cells exhibits a small number of long-lived plasma cells and defective antibody response Pengo et al.

In addition, the survival of memory B cells and their differentiation into plasma cells are affected by autophagic defect in the autophagosome—lysosome fusion as evidenced in Vici syndrome Piano Mortari et al.

The efficiency of vaccines. Some conjugate vaccines have a high antigen-presenting ability to T cells when processed by autophagy. The enhancement of autophagy has been used as an optimized strategy for the development of new vaccines against Japanese encephalitis virus Zhao et al.

When the mycobacterial antigen Ag85B was overexpressed in bacillus Calmette—Guérin vaccine, the vaccine efficacy was improved by augmenting autophagy-mediated antigen presentation Jagannath et al.

Autophagy regulates antimicrobial immunity through multiple pathways and involves different mechanisms such as genetic traits, inflammation, oxidation, apoptosis, and energy metabolism. For example, microbial invasion can cause the release of inflammatory cytokines and ROS generation Tse et al.

Programmed cell death or apoptosis eliminates intracellular pathogens, which is regulated by IAPs, Bcl-2, caspases, nuclear factors, and so forth Liang et al.

There is a complicated network to regulate autophagy-mediated antimicrobial activity, which is validated by representative pathways Figure 3. Signaling pathways mediate the interaction between autophagy and antimicrobial immunity. Microbial invasion triggers the activation of autophagy via different signaling pathways by which multiple cargo receptors or sensors are involved through direct or indirect ways.

Cytosolic constituents are delivered onto PRRs via topological inversion, acting as the antimicrobial effectors of TLRs. For example, viral nucleic acids can be recognized by intracellular sensors to play a crucial role in the initiation of antigen-specific adaptive immunity. Herein, initiation factors and cargo receptors or sensors are integrated into different signaling pathways to modify antimicrobial immunity.

EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; GRP78, glucose-regulated protein 78; GRP94, glucose-regulated protein 94; ORP, oxygen-regulated protein; TSC2, tuberous sclerosis complex 2.

PI3K phosphorylates downstream signal transducers to mediate cell proliferation, differentiation, and intracellular trafficking. The PI3K pathway is activated by innate type I IFN to promote autophagy, which can convert LC3-I to LC3-II for the formation of autophagosomes Schmeisser et al.

AKT is a downstream substrate of PI3K. PI3K is also activated through p-IRS1 and p-IRS2, which results in the subsequent induction of mTORC1 Zoncu et al. The inhibition of mTOR by rapamycin induces autophagy and incurs immunosuppression Fabri et al.

mTOR can repress autophagy by phosphorylating ATG proteins. AMPK is a key energy sensor to integrate intracellular energy metabolism.

AMPK signaling is activated by ATP depletion or glucose starvation, which can induce autophagy through the inhibition of mTORC1 and direct phosphorylation of the protein kinase Unc ULK1 Kim et al.

Both the phosphorylation of AMPK at Thr and the AMPK-dependent phosphorylation of ULK1 at Ser can mediate CDstimulated autophagy and intracellular killing of T. gondii in the infected cells Liu et al.

AMPK-activated autophagy contributes to antibacterial defense against M. tuberculosis by inhibiting the phosphorylation of mTOR in macrophages. AMPK-mediated antimicrobial activity requires the participation of peroxisome proliferator-activated receptor-γ, coactivator 1α PPARGC1A that involves the fusion of phagosomes with LC3B autophagosomes Yang et al.

In macrophages infected with M. tuberculosis , AMPK and PtdIns3K pathways take part in the activation of autophagy induced by antimicrobial LL peptide Rekha et al. During hepatitis C virus HCV infection, the net strength of autophagy depends on the inhibitive effect of AKT on AMPKα. HCV-induced ER stress impedes the AKT—TSC—mTORC1 pathway, contributing to autophagy enhancement Huang et al.

Mechanistic investigation has demonstrated that the activation of AMPK as a new mechanism is influenced by TDRD7 Subramanian et al. A signaling cascade is initiated after external cytokines such as IFNs and ILs as ligands bind to membranous receptors.

Receptor-associated JAKs phosphorylate tyrosine residues and then activate STATs to induce the transcription of target genes Jatiani et al.

There is a cross-regulation between autophagy and type I IFN signaling during host defense. HCV infection can disturb IFN-α signaling and facilitates the escape of HCV from the IFN system, resulting in the persistence of virus infection Luquin et al.

A similar phenomenon is also found in West Nile virus infection. Potential mechanisms involve the inhibition of ISGs e. GBP1 and MxA and the dephosphorylation of STAT1 Harvey et al.

The vita-PAMP of Gram-positive bacteria mediates ER stress via the innate sensor STING, which triggers autophagy activation to engage immune defense and the homeostatic mechanism Figure 1C ; Moretti et al.

If sustained, the UPR can exacerbate inflammation and it has been implicated in pathologies such as obesity, type 1 and type 2 diabetes, cancer, as well as neurodegenerative and autoimmune diseases. In some cases, ER stress is relieved by microbial infection as revealed in the HCV-infected liver Dash et al.

HCV infection stimulates autophagic activity and improves the survival of host cells by inhibiting apoptosis. ER stress-induced cellular apoptosis is also ameliorated by activating autophagy in the macrophages infected by M. tuberculosis Liang et al. ER stress-associated UPR signaling can be elicited by different stimuli such as hypoxia, ischemia, low calcium, and glucose depletion Malhi and Kaufman, ; Wang and Kaufman, ; Dash et al.

The extent and type of UPR signaling usually depend on pathogen species during the infection He, Acute UPR signaling is characterized by returning to baseline level within a short period.

Chronic UPR signaling can maintain a persistent state by regulating the expression levels of some genes. Meanwhile, selective autophagy mediated by PRRs plays a crucial role Fan et al.

However, the extracellular part of an MHC class II molecule i. PRR-mediated degradation improves the efficiency of autophagy, which is the most economical way of the development of adaptive immunity Lin et al. If compensation fails, ER stress-induced apoptosis may be instigated by activating caspase Szegezdi et al.

Microbial pathogens induce ER stress and UPR signaling, which may interact with innate sensors to activate selective autophagy and further regulate the immune defense.

Therefore, the intracellular fate of invading pathogens is determined by the autophagy-mediated antimicrobial immunity Ponpuak and Deretic, ; Deretic, The autophagy-dependent eradication of intracellular T. Microbial invasion activates autophagy to sequestrate adherent-invasive E.

coli via the interaction of ATG16L1 with the complement component C3, resulting in the degradation of pathogens Viret et al. In response to microbial invasion, vital autophagy can shape the host's immunity to mediate the killing of intracellular pathogens. Instead, certain microbial pathogens may adapt autophagy machinery to favor their survival and growth.

At this moment, autophagy becomes a protective mechanism for invading microbes. In host cells infected with M. tuberculosis , autophagic adapter protein p62 delivers cytosolic components into autophagosomes Ponpuak et al.

tuberculosis can block the fusion of phagosome with lysosomes to keep pathogen survival within conventional phagolysosomes Vergne et al. Conversely, the autophagy can be stimulated by reducing cytokines IL-4 and IL in response to M. tuberculosis antigens Ghadimi et al. Also, IFN-β-associated immunoevasion is adopted by M.

tuberculosis , which protects intracellular bacilli. Evidently, autophagy activity regulated by different cytokines affects the survival of pathogens within host cells Sabir et al. Certain bacteria such as S. flexneri and Salmonella typhimurium can escape antibacterial autophagy and immunity by decreasing the level of cytoplasmic C3-ATG16L1 Sorbara et al.

Invasive Shigella secretes IcsB that competitively inhibits the binding of VirG to ATG5, and thus can avoid autophagic degradation Ogawa et al. Intracellular Listeria monocytogenes produces pore-forming toxins to impede the maturation of autophagic vacuoles, through which the bacterial pathogen can replicate in vacuoles and establish persistent infection within host macrophages Birmingham et al.

Autophagy activation may favor the replication of certain viruses. In HCV-infected hepatocytes, autophagy activity is linked to virus replication as reflected by the expression of related proteins such as Beclin-1, ATG4B, ATG5, ATG7, and ATG12 Ke and Chen, Autophagy activation alleviates ER stress and regulates the assembly of infectious virions in host cells Ke and Chen, Autophagy is a vital mechanism responsible for immunomodulation and immunoevasion Dash et al.

Moreover, autophagy machinery promotes hepatocyte growth by enhancing phospho-mTOR and 4EBP1 expression. There is a fine balance between HCV invasion and host cell survival, in which autophagy facilitates HCV replication in hepatocytes and develops infectious persistence and pathogenicity Aizawa et al.

Additionally, HSV-1 protein ICP Autophagy inhibition enables viruses to evade innate immunity and causes lethal encephalitis Orvedahl et al. Dengue virus can usurp autophagy machinery to acquire free fatty acids from lipid droplets, by which a high level of adenosine triphosphate is provided for virus replication Heaton and Randall, Autophagy exerts its unique role to regulate immune homeostasis, which may alter cellular susceptibility to certain pathogens.

Intracellular pathogens can exploit host cells and escape antimicrobial degradation, leading to persistent infection and cell death El-Awady et al. Obviously, the activation of autophagy acts as double-edged sword, contributing to not only the elimination of pathogens but also immunoevasion and pathogen survival.

The perplexing interaction between microbial invasion and autophagic adaptation governs the immunoregulation and controls the final outcome of the host—microbe encounter Deretic and Levine, During microbial infection, the host cell adjusts its biomass and function by regulating the autophagy machinery, which involves energy supplementation, modification of innate and adaptive immunity, proliferation, apoptosis, etc.

Intracellular pathogens may be eradicated via the autophagic defense mechanism. Alternatively, autophagy machinery can be adapted or subverted to cause persistent infection. By altering or evading autophagy, intracellular invaders can cause host cell death.

The pathophysiological manifestations depend on the comprehensive regulation between autophagy and antimicrobial immunity Yordy et al.

The duality of autophagy means that it may have beneficial and harmful effects on the process of antimicrobial immunity. The dual effect of autophagy depends on the trait or nature of microbial pathogens, which has been characterized in the pathogenesis of certain chronic infections such as hepatitis, AIDS, and tuberculosis.

When those diseases are treated using autophagy-related medicines, the option of treatment protocols should consider different stages or conditions.

For instance, HBV or HBV X protein can activate autophagy in the initial stage, but inhibits subsequent degradation by impairing lysosomal acidification Khabir et al. When the autophagy strategy is utilized to treat HBV infection, the pros and cons of autophagy must be weighed.

HDV can alter the autophagic process in the elongation stage to promote genome replication. Also, the pathophysiological characteristics of clinical disease should be considered. For example, the stable knockdown of several autophagy factors can achieve synergistic inhibition on HIV-1 replication Eekels et al.

Autophagy thus is a therapeutic target against HIV-1 infection. tuberculosis or opportunistic pathogens. It is necessary to explore novel strategies under the coinfection of HIV-1 and M.

A few drugs such as vitamin D3, trehalose, and phenylbutyrate may be helpful Rekha et al. Essential autophagy modulates both cell survival and death as evidenced through mitochondrial mediation. Mitophagy is a selective degradation of old or damaged mitochondria to maintain survival state.

The mitochondrion-dependent pathway is also a well-known mechanism for apoptotic cell death Wang, There is a negative feedback loop including FADD and caspase-8, which modulates autophagic response Walsh and Bell, Anti-apoptotic Bcl-2 negatively regulates Beclinmediated autophagy and modifies antimicrobial immunity Casalino-Matsuda et al.

Autophagy takes part in the degradation of pathogens and subsequent antigen presentation. Apoptosis signaling can provide feedback regulation for autophagic response. The interaction between apoptosis and autophagy is a critical modulator for the functional state of host cells. Excessive apoptosis caused by microbial infection can impair organ function.

Therefore, autophagy affects functional maintenance of the infected organ. Autophagic response can activate or antagonize apoptosis, obviously, playing a dual role Wang, Necroptosis and pyroptosis are implicated in cell death as well. The immunogenicity of necroptotic death is a novel strategy for developing cancer vaccines Lin et al.

The autophagy machinery participates in cytokine storm that destroys a lot of cells in a short time during chimeric antigen receptor T-cell therapy or COVID infection DeFrancesco, ; Meftahi et al.

The autophagy pathway modulated by diverse factors such as IFNs, NLRs, downstream effectors, and substrates may skew the immune response to induce immunoevasion and immunosuppression. There is a complex network to regulate autophagy, which impacts on the performance of antimicrobial immunity.

If we consider microbial invasion as the initial input and antimicrobial immunity as the integrative output, the regulation of autophagy is pivotal to controlling the host—pathogen balance. Up to now, the regulation of the autophagic process is not fully understood.

Moreover, autophagy is related to distinct mechanisms such as oxidative stress, energy metabolism, protein synthesis, and apoptosis.

All those mechanisms should be comprehensively considered since they are not in vectorial or parallel ways. A long-term effort is needed to clarify the details of autophagy regulation.

The invasion of microbial pathogens activates autophagy in host cells. Autophagy activation modifies downstream immune responses. Due to the duality of autophagy, antimicrobial immunity may be enhanced or weakened.

The outcomes of autophagy-mediated immune response are varied, depending on the categories of microbial pathogens and the types of infected cells. Therefore, the antimicrobial application of the autophagy mechanism must consider pathogen characteristics as well as cell types. The administration of autophagy modulators e.

chloroquine and hydroxychloroquine has shown therapeutic benefits in certain infectious diseases e. malaria, amebiasis, and Q fever. Furthermore, the mTOR pathway is the potential target against viral pathogens.

Yet, mTOR also participates in the replication and release of virions Maiese, Autophagy modulators can be combined with immunomodulators based on the mechanistic autophagy—immunity axis Wang et al.

Hopefully, the best therapeutic effect may be achieved through drug combination. Autophagy is the core mechanism of regulating antimicrobial immunity. Functional analysis shows that autophagy can control pathophysiological manifestations of microbial infection and determine the choice of clinical treatment protocols, especially in the case of coinfection.

Different infections or different stages of the same infection require respective protocols, considering the dual nature of autophagy. A few therapeutic agents, based on the autophagy mechanism, have been used in clinical practice.

The accumulated evidence confirms their positive effects. There is a bright future for the development of autophagy-related drugs against microbial infections. This work was supported by grants from Beijing Natural Science Foundation , National Key Research and Development Project YFA , and Chinese Academy of Medical Sciences CAMS Innovation Fund for Medical Sciences CIFMS, I2M Author contributions: C.

and K. conceived and designed the manuscript. were responsible for data collection and analysis. Additional data were provided by Y. and L. wrote the first draft, which was revised by C.

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