Autophagy and immunity -
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.
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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.
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA. langr bcm. This Site. Google Scholar.
Tony Eissa N. Tony Eissa. J Innate Immun 12 1 : 21— Article history Received:. Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. View large Download slide. The authors have no ethical conflicts to disclose.
The authors have no conflicts of interest to declare. From Christian de Duve to Yoshinori Ohsumi: more to autophagy than just dining at home. Search ADS. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages.
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Deacetylation of nuclear LC3 drives autophagy initiation under starvation. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Acetylation of Beclin 1 inhibits autophagosome maturation and promotes tumour growth. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB.
A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. The E3 ubiquitin ligase STUB1 regulates autophagy and mitochondrial biogenesis by modulating TFEB activity.
Response of cultured macrophages to Mycobacterium tuberculosis, with observations on fusion of lysosomes with phagosomes. Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase.
Mycobacterium tuberculosis glycosylated phosphatidylinositol causes phagosome maturation arrest. Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis. Mycobacterium tuberculosis blocks crosslinking of annexin-1 and apoptotic envelope formation on infected macrophages to maintain virulence.
Virulent clinical isolates of Mycobacterium tuberculosis grow rapidly and induce cellular necrosis but minimal apoptosis in murine macrophages. Nitazoxanide stimulates autophagy and inhibits mTORC1 signaling and intracellular proliferation of Mycobacterium tuberculosis. Harnessing of TLR-mediated autophagy to combat mycobacteria in macrophages.
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Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin.
Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. Autophagy regulates phagocytosis by modulating the expression of scavenger receptors.
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Secrets of a successful pathogen: legionella resistance to progression along the autophagic pathway. Association of Legionella pneumophila with the macrophage endoplasmic reticulum. Loss of Dictyostelium ATG9 results in a pleiotropic phenotype affecting growth, development, phagocytosis and clearance and replication of Legionella pneumophila.
The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Legionella pneumophila S1P-lyase targets host sphingolipid metabolism and restrains autophagy. Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes.
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Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Abdel Fattah.
Critical role for IL in spontaneous lung inflammation caused by autophagy deficiency. The lung is protected from spontaneous inflammation by autophagy in myeloid cells. Autophagy deficiency in macrophages enhances NLRP3 inflammasome activity and chronic lung disease following silica exposure.
Homeostatic Control of Innate Lung Inflammation by Vici Syndrome Gene Epg5 and Additional Autophagy Genes Promotes Influenza Pathogenesis. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation.
Unique role for ATG5 in neutrophil-mediated immunopathology during M. NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria.
Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection.
Karger AG, Basel. This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4. Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. During starvation or certain forms of stress, cells use autophagy to digest and recycle large, non-specific parts of their cytoplasm.
However, autophagy can also be used to spatiotemporally regulate immune signaling pathways e. by recycling activated proteins to limit cytokine production and block inflammation e.
by removing damaged mitochondria before they can release harmful reactive oxygen species. To isolate and remove specific threats, cells use a selective form of autophagy in which the targeted cargo must first be tagged by ubquitination. The ubiquitinated cargo is then dragged and bound to the isolation membrane via LC3 by one of various sequestosome-like proteins SLRs such as p62, optineurin, Parkin or PINK1.
Selective autophagy of mitochondria is known as mitophagy, whereas that of pathogens is known as xenophagy. Autophagy has been extensively linked to innate immune signaling pathways—for example, during cellular responses to damage-associated molecular patterns DAMPs and pathogen-associated molecular patterns PAMPs.
In fact, autophagy regulates, and is regulated by, pattern recognition receptors PRRs such as Toll-like receptors TLRs , Nod-like receptors NLRs , RIG-I-like receptors RLRs , cytosolic DNA sensors CDS and Stimulator of Interferon Genes STING as well as inflammasomes.
This interplay encompasses positive as well as negative regulatory mechanisms that ensure acute inflammatory responses while preventing hyperinflammation. The TLRs comprise cell-surface TLR1, TLR2, TLR4 and TLR6 and endosomal TLR3, TLR7, TLR8, TLR9 and TLR13 receptors, each of which responds to cognate DAMPs and PAMPs of self, pathogenic or tumoral origin.
Representative TLR ligands include bacterial compounds such as lipopolysaccharide LPS; TLR4 , flagellin TLR5 and peptidoglycans TLR2 ; and nucleic acids such as DNA TLR9 and RNA TLR3, TLR7, TLR8 and TLR Activation of TLRs leads to production of pro-inflammatory cytokines and, in some cases, to production of type I interferons IFNs.
TLRs have been shown to promote autophagy: in fact, several groups have reported the induction of autophagy by signaling through TLR4, TLR7, TLR3, TLR2 or TLR5 TLR-induced autophagy appears to depend on the adaptor proteins MyD88 and TRIF; in both cases, via direct interaction with Beclin 1 6.
TLR ligands stimulate formation of autophagosomes and autolysosomes in immune cells such as macrophages 7 , and TLR-induced autophagy has been demonstrated in vivo, in murine models of bacterial and viral infection 8.
The autophagic machinery can deliver DNA and RNA to endosomal TLRs. In fact, autophagy and a closely related process, LC3-associated phagocytosis LAP have each been reported to be required for recognition of nucleic acids by TLR7 and TLR9 in dendritic cells 7.
Intriguingly, TLR-induced autophagy has also been implicated in certain diseases. For instance, TLR3- and TLR4-induced autophagy have been linked to the migration and invasiveness of lung cancer cells 9. Other innate immune receptors have been described to work in concert with autophagy, and this is likely to be cell-type specific 10, These include the cytoplasmic receptors, Nucleotide-binding Oligomerization Domain-containing protein 1 and 2 NOD1 and NOD2 , which sense the bacterial peptidoglycan derivatives D-glutamyl-meso-diaminopimelic acid iE-DAP and muramyl dipeptide MDP , respectively.
In macrophages, NOD1 and NOD2 interact with Atg16L1 and signal to induce autophagy, and in dendritic cells, activation of NOD2 by bacterial ligands leads to generation of autophagosomes 7.
In turn, STING drives production of type I IFNs and pro-inflammatory cytokines. STING can also be directly activated by cyclic dinucleotides CDNs released into the cytoplasm by invading microbes.
For example, it triggers both autophagy and type I IFN production during M. tuberculosis infection 7 , and has been reported to be required for selective autophagy of this pathogen Furthermore, following activation, STING seems to be trafficked from the endoplasmic reticulum to the Golgi by an autophagy-like process that depends on Atg9a 7.
Intriguingly, cGAS has been reported to be degraded by pdependent selective autophagy after it senses cytoplasmic DNA Interestingly, the cytoplasmic DNA sensor AIM2 has been reported to inhibit STING-induced autophagy during M.
bovis infection There have been reports that cGAS and STING each interacts with autophagy proteins in other contexts, although the nature of these interactions remains opaque. Moreover, trafficking of STING appears to involve Atg9a The innate immune arsenal also includes the RIG-I-Like receptors RLRs , which respond to cytoplasmic self or foreign RNA, including viral RNA.
The principal RLRs are RIG-I, which detects shorter dsRNA, and MDA-5, which detects longer dsRNA. Upon activation, each of these activates the adaptor protein MAVS, which then induces type I IFNs and pro-inflammatory cytokines. Although very little is known about the interactions between RLRs and autophagy, there is evidence that autophagy proteins can negatively regulate RLRs to limit type production of I IFNs following detection of self or foreign RNA in the cytoplasm.
For example, a conjugate of the autophagy proteins Atg5 and Atg12 interfere with signaling between dsRNA sensors MDA5 or RIG-I and the adaptor protein MAVS Similarly, ubiquitin-specific protease 19 USP19 , which has been described as a positive regulator of autophagy, has been shown to inhibit the interaction between RIG-I and MAVS in a Beclindependent fashion, which results in diminished IFN signaling Inflammasomes are complexes that comprise an innate immune sensor either AIM2, NLRP1, NLRP3 or NLRC4 , plus the adaptor protein Apoptosis-associated Speck-like protein containing a CARD ASC , and pro-Caspase 1.
Each inflammasome is named after its constituent sensor. Inflammasomes are crucial for generating inflammatory responses to DAMPs and PAMPs such as cytosolic DNA AIM2 , MDP NLRP1 , uric acid NLRP3 and flagellin NLRC4. Activation of inflammasomes induces predecessors of the inflammatory interleukins IL-1 and IL Autophagy has been demonstrated to regulate activation of inflammasomes as a way to limit inflammation.
It can do this directly by either digesting the interleukin precursors e. 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.
Molecular Cancer Autophagy and immunity 18Immunity number: 17 Immmunity this article. Metrics details. Autophagy Ketosis and Hormonal Balance a genetically well-controlled Autophaagy process that is tightly controlled ikmunity a set of core genes, Autophagy and immunity the Autophagy and immunity of autophagy-related genes ATG. It can promote or suppress tumor development, which depends on the cell and tissue types and the stages of tumor. At present, tumor immunotherapy is a promising treatment strategy against tumors. Recent studies have shown that autophagy significantly controls immune responses by modulating the functions of immune cells and the production of cytokines. Conversely, some cytokines and immune cells have a great effect on the function of autophagy.
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