Autophagy-mediated regulation of neutrophils and clinical applications

Abstract

Autophagy, an adaptive catabolic process, plays a cytoprotective role in enabling cellular homeostasis in the innate and adaptive immune systems. Neutrophils, the most abundant immune cells in circulation, are professional killers that orchestrate a series of events during acute inflammation. The recent literature indicates that autophagy has important roles in regulating neutrophil functions, including differentiation, degranulation, metabolism and neutrophil extracellular trap formation, that dictate neutrophil fate. It is also becoming increasingly clear that autophagy regulation is critical for neutrophils to exert their immunological activity. However, evidence regarding the systematic communication between neutrophils and autophagy is insufficient. Here, we provide an updated overview of the function of autophagy as a regulator of neutrophils and discuss its clinical relevance to provide novel insight into potentially relevant treatment strategies.

Keywords

Autophagy / Neutrophil / Innate immunity / NETs / Clinical application / Neutrophil extracellular trap

References

[1] Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11: 519-31.

[2] Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol 2011; 12: 1035-44.

[3] de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol 2016; 16: 378-91.

[4] Nauseef WM, Borregaard N. Neutrophils at work. Nat Immunol 2014; 15: 602-11.

[5] Nicolas-Avila JA, Adrover JM, Hidalgo A. Neutrophils in homeostasis, immunity, and cancer. Immunity 2017; 46: 15-28.

[6] Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med 2013; 368: 1845-6.

[7] Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 2011; 27: 107-32.

[8] Codogno P, Mehrpour M, Proikas-Cezanne T. Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat Rev Mol Cell Biol 2011; 13: 7-12.

[9] Mizushima N.Autophagy: process and function. Genes Dev 2007; 21: 2861-73.

[10] Huang J, Brumell JH. Bacteria-autophagy interplay: a battle for survival. Nat Rev Microbiol 2014; 12: 101-14.

[11] Deretic V, Saitoh T, Akira S. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 2013; 13: 722-37.

[12] Gong L, Devenish RJ, Prescott M. Autophagy as a macrophage response to bacterial infection. IUBMB Life 2012; 64: 740-7.

[13] Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011; 147: 728-41.

[14] Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 2018; 19: 349-64.

[15] Narni-Mancinelli E, Soudja SM, Crozat K, Dalod M, Gounon P, Geissmann F, et al. Inflammatory monocytes and neutrophils are licensed to kill during memory responses in vivo. PLoS Pathog 2011; 7: e1002457.

[16] Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 2014; 20: 460-73.

[17] Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, et al. FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J Cell Biol 2008; 181: 497-510.

[18] Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N. Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 2009; 5: 973-9.

[19] Itakura E, Kishi C, Inoue K, Mizushima N. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 2008; 19: 5360-72.

[20] Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 2009; 11: 385-96.

[21] Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 2008; 19: 2092-100.

[22] Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 2013; 15: 741-50.

[23] Egan DF, Chun MG, Vamos M, Zou H, Rong J, Miller CJ, et al. Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates. Mol Cell 2015; 59: 285-97.

[24] Ge L, Melville D, Zhang M, Schekman R. The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. Elife 2013; 2: e00947.

[25] Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 2010; 141: 656-67.

[26] Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, et al. Autophagosomes form at ER-mitochondria contact sites. Nature 2013; 495: 389-93.

[27] Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol 2009; 11: 1433-7.

[28] Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol 2010; 12: 747-58.

[29] Proikas-Cezanne T, Takacs Z, Donnes P, Kohlbacher O. WIPI proteins: Essential PtdIns3P effectors at the nascent autophagosome. J Cell Sci 2015; 128: 207-17.

[30] Orsi A, Razi M, Dooley HC, Robinson D, Weston AE, Collinson LM, et al. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol Biol Cell 2012; 23: 1860-73.

[31] Young AR, Chan EY, Hu XW, Kochl R, Crawshaw SG, High S, et al. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J Cell Sci 2006; 119: 3888-900.

[32] Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, et al. A ubiquitin-like system mediates protein lipidation. Nature 2000; 408: 488-92.

[33] Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, et al. The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J Cell Biol 2000; 151: 263-76.

[34] Shibutani ST, Saitoh T, Nowag H, Munz C, Yoshimori T. Autophagy and autophagy-related proteins in the immune system. Nat Immunol 2015; 16: 1014-24.

[35] Mizushima N, Sugita H, Yoshimori T, Ohsumi Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem 1998; 273: 33889-92.

[36] Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 2004; 36: 2503-18.

[37] Nakatogawa H, Ichimura Y, Ohsumi Y.Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 2007; 130: 165-78.

[38] Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, et al. Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 2004; 117: 4837-48.

[39] Itakura E, Kishi-Itakura C, Mizushima N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 2012; 151: 1256-69.

[40] Tanaka Y, Guhde G, Suter A, Eskelinen EL, Hartmann D, Lullmann-Rauch R, et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 2000; 406: 902-6.

[41] Eskelinen EL, Illert AL, Tanaka Y, Schwarzmann G, Blanz J, Von Figura K, et al. Role of LAMP-2 in lysosome biogenesis and autophagy. Mol Biol Cell 2002; 13: 3355-68.

[42] Chrysanthopoulou A, Kambas K, Stakos D, Mitroulis I, Mitsios A, Vidali V, et al. Interferon lambda1/IL-29 and inorganic polyphosphate are novel regulators of neutrophil-driven thromboinflammation. J Pathol 2017; 243: 111-22.

[43] Ullah I, Ritchie ND, Evans TJ. The interrelationship between phagocytosis, autophagy and formation of neutrophil extracellular traps following infection of human neutrophils by Streptococcus pneumoniae. Innate Immun 2017; 23: 413-23.

[44] Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 2014; 15: 81-94.

[45] Ferguson TA, Green DR. Autophagy and phagocytosis converge for better vision. Autophagy 2014; 10: 165-7.

[46] Borregaard N.Neutrophils, from marrow to microbes. Immunity 2010; 33: 657-70.

[47] Riffelmacher T, Clarke A, Richter FC, Stranks A, Pandey S, Danielli S, et al. Autophagy-dependent generation of free fatty acids is critical for normal neutrophil differentiation. Immunity 2017; 47: 466-80 e5.

[48] Ishii T, Hosoki K, Nikura Y, Yamashita N, Nagase T, Yamashita N. IFN regulatory factor 3 potentiates emphysematous aggravation by lipopolysaccharide. J Immunol 2017; 198: 3637-49.

[49] Rozman S, Yousefi S, Oberson K, Kaufmann T, Benarafa C, Simon HU. The generation of neutrophils in the bone marrow is controlled by autophagy. Cell Death Differ 2015; 22: 445-56.

[50] Leveque-El Mouttie L, Vu T, Lineburg KE, Kuns RD, Bagger FO, Teal BE, et al. Autophagy is required for stem cell mobilization by G-CSF. Blood 2015; 125: 2933-6.

[51] Trocoli A, Mathieu J, Priault M, Reiffers J, Souquere S, Pierron G, et al. ATRA-induced upregulation of Beclin 1 prolongs the life span of differentiated acute promyelocytic leukemia cells. Autophagy 2011; 7: 1108-14.

[52] Jin J, Britschgi A, Schlafli AM, Humbert M, Shan-Krauer D, Batliner J, et al. Low autophagy (ATG) gene expression is associated with an immature AML blast cell phenotype and can be restored during AML differentiation therapy. Oxid Med Cell Longev 2018; 2018: 1482795.

[53] Brigger D, Proikas-Cezanne T, Tschan MP. WIPI-dependent autophagy during neutrophil differentiation of NB4 acute promyelocytic leukemia cells. Cell Death Dis 2014; 5: e1315.

[54] Haimovici A, Brigger D, Torbett BE, Fey MF, Tschan MP. Induction of the autophagy-associated gene MAP1S via PU.1 supports APL differentiation. Leuk Res 2014; 38: 1041-7.

[55] Humbert M, Mueller C, Fey MF, Tschan MP. Inhibition of damage-regulated autophagy modulator-1 (DRAM-1) impairs neutrophil differentiation of NB4 APL cells. Leuk Res 2012; 36: 1552-6.

[56] Dyugovskaya L, Berger S, Polyakov A, Lavie P, Lavie L. Intermittent hypoxia affects the spontaneous differentiation in vitro of human neutrophils into long-lived Giant phagocytes. Oxid Med Cell Longev 2016; 2016: 9636937.

[57] Oral O, Oz-Arslan D, Itah Z, Naghavi A, Deveci R, Karacali S, et al. Cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death. Apoptosis 2012; 17: 810-20.

[58] Luo S, Rubinsztein DC. Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ 2010; 17: 268-77.

[59] Hu R, Chen ZF, Yan J, Li QF, Huang Y, Xu H, et al. Endoplasmic reticulum stress of neutrophils is required for ischemia/reperfusion-induced acute lung injury. J Immunol 2015; 195: 4802-9.

[60] Xu F, Zhang C, Zou Z, Fan EKY, Chen L, Li Y, et al. Aging-related Atg5 defect impairs neutrophil extracellular traps formation. Immunology 2017; 151: 417-32.

[61] Pliyev BK, Menshikov M. Differential effects of the autophagy inhibitors 3-methyladenine and chloroquine on spontaneous and TNF-alpha-induced neutrophil apoptosis. Apoptosis 2012; 17: 1050-65.

[62] Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ 2018; 25: 486-541.

[63] Horn J, Stelzner K, Rudel T, Fraunholz M. Inside job: Staphylococcus aureus host-pathogen interactions. Int J Med Microbiol 2018; 308: 307-24.

[64] Lavie L, Dyugovskaya L, Polyakov A, Rogovoy O, Leder E.Development and identification of a novel subpopulation of human neutrophil-derived Giant phagocytes in vitro. J Vis Exp 2017; 119.

[65] Dyugovskaya L, Berger S, Polyakov A, Lavie L. The development of giant phagocytes in long-term neutrophil cultures. J Leukoc Biol 2014; 96: 511-21.

[66] Bhattacharya A, Wei Q, Shin JN, Abdel Fattah E, Bonilla DL, Xiang Q, et al. Autophagy is required for neutrophil-mediated inflammation. Cell Rep 2015; 12: 1731-9.

[67] Borregaard N.Development of neutrophil granule diversity. Ann N Y Acad Sci 1997; 832: 62-8.

[68] Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annu Rev Immunol 2012; 30: 459-89.

[69] Cools-Lartigue J, Spicer J, Najmeh S, Ferri L. Neutrophil extracellular traps in cancer progression. Cell Mol Life Sci 2014; 71: 4179-94.

[70] Cooper PR, Palmer LJ, Chapple IL. Neutrophil extracellular traps as a new paradigm in innate immunity: friend or foe? Periodontol 2000 2013; 63: 165-97.

[71] Remijsen Q, Kuijpers TW, Wirawan E, Lippens S, Vandenabeele P, Vanden Berghe T. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ 2011; 18: 581-8.

[72] Kambas K, Mitroulis I, Ritis K. The emerging role of neutrophils in thrombosis-the journey of TF through NETs. Front Immunol 2012; 3: 385.

[73] Mohammed BM, Fisher BJ, Kraskauskas D, Farkas D, Brophy DF, Fowler AA, 3rd, et al. Vitamin C: a novel regulator of neutrophil extracellular trap formation. Nutrients 2013; 5: 3131-51.

[74] Itakura A, McCarty OJ. Pivotal role for the mTOR pathway in the formation of neutrophil extracellular traps via regulation of autophagy. Am J Physiol Cell Physiol 2013; 305: C348-54.

[75] Iba T, Hashiguchi N, Nagaoka I, Tabe Y, Murai M. Neutrophil cell death in response to infection and its relation to coagulation. J Intensive Care 2013; 1: 13.

[76] Maueroder C, Schall N, Meyer F, Mahajan A, Garnier B, Hahn J, et al. Capability of neutrophils to form NETs is not directly influenced by a CMA-targeting peptide. Front Immunol 2017; 8: 16.

[77] Park SY, Shrestha S, Youn YJ, Kim JK, Kim SY, Kim HJ, et al. Autophagy primes neutrophils for neutrophil extracellular trap formation during sepsis. Am J Respir Crit Care Med 2017; 196: 577-89.

[78] Germic N, Stojkov D, Oberson K, Yousefi S, Simon HU.Neither eosinophils nor neutrophils require ATG5-dependent autophagy for extracellular DNA trap formation. Immunology 2017; 152: 517-25.

[79] Sha LL, Wang H, Wang C, Peng HY, Chen M, Zhao MH. Autophagy is induced by anti-neutrophil cytoplasmic abs and promotes neutrophil extracellular traps formation. Innate Immun 2016; 22: 658-65.

[80] Wang L, Law HK. The role of autophagy in lupus nephritis. Int J Mol Sci 2015; 16: 25154-67.

[81] Pan Q, Gao C, Chen Y, Feng Y, Liu WJ, Liu HF. Update on the role of autophagy in systemic lupus erythematosus: s novel therapeutic target. Biomed Pharmacother 2015; 71: 190-3.

[82] Sharma A, Simonson TJ, Jondle CN, Mishra BB, Sharma J. Mincle-mediated neutrophil extracellular trap formation by regulation of autophagy. J Infect Dis 2017; 215: 1040-8.

[83] Kenno S, Perito S, Mosci P, Vecchiarelli A, Monari C. Autophagy and reactive oxygen species are involved in neutrophil extracellular traps release induced by C. albicans morphotypes. Front Microbiol 2016; 7: 879.

[84] Tang S, Zhang Y, Yin SW, Gao XJ, Shi WW, Wang Y, et al. Neutrophil extracellular trap formation is associated with autophagy-related signalling in ANCA-associated vasculitis. Clin Exp Immunol 2015; 180: 408-18.

[85] Mitroulis I, Kambas K, Chrysanthopoulou A, Skendros P, Apostolidou E, Kourtzelis I, et al. Neutrophil extracellular trap formation is associated with IL-1beta and autophagy-related signaling in gout. PLoS One 2011; 6: e29318.

[86] Remijsen Q, Vanden Berghe T, Wirawan E, Asselbergh B, Parthoens E, De Rycke R, et al. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Cell Res 2011; 21: 290-304.

[87] Villagra-Blanco R, Silva LMR, Gartner U, Wagner H, Failing K, Wehrend A, et al. Molecular analyses on Neospora caninum-triggered NETosis in the caprine system. Dev Comp Immunol 2017; 72: 119-27.

[88] Angelidou I, Chrysanthopoulou A, Mitsios A, Arelaki S, Arampatzioglou A, Kambas K, et al. REDD1/autophagy pathway is associated with neutrophil-driven IL-1beta inflammatory response in active ulcerative colitis. J Immunol 2018; 200: 3950-61.

[89] Konstantinidis T, Kambas K, Mitsios A, Panopoulou M, Tsironidou V, Dellaporta E, et al. Immunomodulatory role of clarithromycin in Acinetobacter baumannii infection via formation of neutrophil extracellular traps. Antimicrob Agents Chemother 2016; 60: 1040-8.

[90] Maugeri N, Campana L, Gavina M, Covino C, De Metrio M, Panciroli C, et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost 2014; 12: 2074-88.

[91] Cheng ML, Ho HY, Lin HY, Lai YC, Chiu DT. Effective NET formation in neutrophils from individuals with G6PD Taiwan-Hakka is associated with enhanced NADP(+) biosynthesis. Free Radic Res 2013; 47: 699-709.

[92] Kambas K, Mitroulis I, Apostolidou E, Girod A, Chrysanthopoulou A, Pneumatikos I, et al. Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. PLoS One 2012; 7: e45427.

[93] Boone BA, Orlichenko L, Schapiro NE, Loughran P, Gianfrate GC, Ellis JT, et al. The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer. Cancer Gene Ther 2015; 22: 326-34.

[94] Dan Dunn J, Alvarez LA, Zhang X, Soldati T. Reactive oxygen species and mitochondria: s nexus of cellular homeostasis. Redox Biol 2015; 6: 472-85.

[95] Manda-Handzlik A, Bystrzycka W, Wachowska M, Sieczkowska S, Stelmaszczyk-Emmel A, Demkow U, et al. The influence of agents differentiating HL-60 cells toward granulocyte-like cells on their ability to release neutrophil extracellular traps. Immunol Cell Biol 2018; 96: 413-25.

[96] Suzuki E, Maverakis E, Sarin R, Bouchareychas L, Kuchroo VK, Nestle FO, et al. T cell-independent mechanisms associated with neutrophil extracellular trap formation and selective autophagy in IL-17A-mediated epidermal hyperplasia. J Immunol 2016; 197: 4403-12.

[97] Paiva CN, Bozza MT. Are reactive oxygen species always detrimental to pathogens? Antioxid Redox Signal 2014; 20: 1000-37.

[98] Chargui A, El May MV. Autophagy mediates neutrophil responses to bacterial infection. APMIS 2014; 122: 1047-58.

[99] Avagliano L, Massa V, Zullino S, Doi P, Marconi AM, Ferrazzi E, et al. Inflammation modulates LC3 expression in human preterm delivery. J Matern Fetal Neonatal Med 2017; 30: 698-704.

[100] Pieterse E, Rother N, Yanginlar C, Hilbrands LB, van der Vlag J. Neutrophils discriminate between lipopolysaccharides of different bacterial sources and selectively release neutrophil extracellular traps. Front Immunol 2016; 7: 484.

[101] Ramachandran G, Gade P, Tsai P, Lu W, Kalvakolanu DV, Rosen GM, et al. Potential role of autophagy in the bactericidal activity of human PMNs for Bacillus anthracis. Pathog Dis 2015; 73: ftv080.

[102] Wang C, Mendonsa GR, Symington JW, Zhang Q, Cadwell K, Virgin HW, et al. Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo. Proc Natl Acad Sci U S A 2012; 109: 11008-13.

[103] Kanayama M, Inoue M, Danzaki K, Hammer G, He YW, Shinohara ML. Autophagy enhances NFkappaB activity in specific tissue macrophages by sequestering A20 to boost antifungal immunity. Nat Commun 2015; 6: 5779.

[104] Torraca V, Mostowy S. Zebrafish infection: from pathogenesis to cell biology. Trends Cell Biol 2018; 28: 143-56.

[105] O’Keeffe KM, Wilk MM, Leech JM, Murphy AG, Laabei M, Monk IR, et al. Manipulation of autophagy in phagocytes facilitates Staphylococcus aureus bloodstream infection. Infect Immun 2015; 83: 3445-57.

[106] Chargui A, Cesaro A, Mimouna S, Fareh M, Brest P, Naquet P, et al. Subversion of autophagy in adherent invasive Escherichia coli-infected neutrophils induces inflammation and cell death. PLoS One 2012; 7: e51727.

[107] Rinchai D, Riyapa D, Buddhisa S, Utispan K, Titball RW, Stevens MP, et al. Macroautophagy is essential for killing of intracellular Burkholderia pseudomallei in human neutrophils. Autophagy 2015; 11: 748-55.

[108] Horn J, Stelzner K, Rudel T, Fraunholz M. Inside job: Staphylococcus aureus host-pathogen interactions. Int J Med Microbiol 2018; 308: 607-24.

[109] Pfeiler S, Khandagale AB, Magenau A, Nichols M, Heijnen HF, Rinninger F, et al. Distinct surveillance pathway for immunopathology during acute infection via autophagy and SR-BI. Sci Rep 2016; 6: 34440.

[110] Kimmey JM, Huynh JP, Weiss LA, Park S, Kambal A, Debnath J, et al. Unique role for ATG5 in neutrophil-mediated immunopathology during M. tuberculosis infection. Nature 2015; 528: 565-9.

[111] Deretic V, Jiang S, Dupont N. Autophagy intersections with conventional and unconventional secretion in tissue development, remodeling and inflammation. Trends Cell Biol 2012; 22: 397-406.

[112] Sanjuan MA, Dillon CP, Tait SW, Moshiach S, Dorsey F, Connell S, et al. Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 2007; 450: 1253-7.

[113] Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, Scapozza L, et al. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol 2006; 8: 1124-32.

[114] Young MM, Takahashi Y, Khan O, Park S, Hori T, Yun J, et al. Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J Biol Chem 2012; 287: 12455-68.

[115] Behrends C, Sowa ME, Gygi SP, Harper JW. Network organization of the human autophagy system. Nature 2010; 466: 68-76.

[116] Zhu L, Yang J, Zhang J, Peng B. The presence of autophagy in human periapical lesions. J Endod 2013; 39: 1379-84.

[117] Qian M, Fang X, Wang X. Autophagy and inflammation. Clin Transl Med 2017; 6: 24.

[118] Liu CH, Liu H, Ge B. Innate immunity in tuberculosis: host defense vs pathogen evasion. Cell Mol Immunol 2017; 14: 963-75.

[119] Xu XC, Wu YF, Zhou JS, Chen HP, Wang Y, Li ZY, et al. Autophagy inhibitors suppress environmental particulate matter-induced airway inflammation. Toxicol Lett 2017; 280: 206-12.

[120] Gabrion A, Hmitou I, Moshous D, Neven B, Lefevre-Utile A, Diana JS, et al. Mammalian target of rapamycin inhibition counterbalances the inflammatory status of immune cells in patients with chronic granulomatous disease. J Allergy Clin Immunol 2017; 139: 1641-9 e6.

[121] Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer 2016; 16: 431-46.

[122] Li XF, Chen DP, Ouyang FZ, Chen MM, Wu Y, Kuang DM, et al. Increased autophagy sustains the survival and pro-tumourigenic effects of neutrophils in human hepatocellular carcinoma. J Hepatol 2015; 62: 131-9.

[123] Matsuo H, Itoh H, Kitamura N, Kamikubo Y, Higuchi T, Shiga S, et al. Intravenous immunoglobulin enhances the killing activity and autophagy of neutrophils isolated from immunocompromised patients against multidrug-resistant bacteria. Biochem Biophys Res Commun 2015; 464: 94-9.

[124] Vyas SP, Goswami R. Striking the right immunological balance prevents progression of tuberculosis. Inflamm Res 2017; 66: 1031-56.

[125] Vural A, Kehrl JH. Autophagy in macrophages: Impacting inflammation and bacterial infection. Scientifica (Cairo) 2014; 2014: 825463.

[126] Zhao J, Sun Y, Shi P, Dong JN, Zuo LG, Wang HG, et al. Celastrol ameliorates experimental colitis in IL-10 deficient mice via the up-regulation of autophagy. Int Immunopharmacol 2015; 26: 221-8.

[127] Cappello AR, Curcio R, Lappano R, Maggiolini M, Dolce V. The physiopathological role of the exchangers belonging to the SLC37 family. Front Chem 2018; 6: 122.

[128] Jin L, Batra S, Jeyaseelan S. Deletion of Nlrp3 augments survival during polymicrobial sepsis by decreasing autophagy and enhancing phagocytosis. J Immunol 2017; 198: 1253-62.

[129] Zhu Q, Wang H, Wang H, Luo Y, Yu Y, Du Q, et al. Protective effects of ethyl pyruvate on lipopolysaccharide induced acute lung injury through inhibition of autophagy in neutrophils. Mol Med Rep 2017; 15: 1272-8.

[130] Manfredi AA, Rovere-Querini P, D’Angelo A, Maugeri N. Low molecular weight heparins prevent the induction of autophagy of activated neutrophils and the formation of neutrophil extracellular traps. Pharmacol Res 2017; 123: 146-56.

[131] Itoh H, Matsuo H, Kitamura N, Yamamoto S, Higuchi T, Takematsu H, et al. Enhancement of neutrophil autophagy by an IVIG preparation against multidrug-resistant bacteria as well as drug-sensitive strains. J Leukoc Biol 2015; 98: 107-17.

[132] Yu X, Li C, Hong W, Pan W, Xie J. Autophagy during Mycobacterium tuberculosis infection and implications for future tuberculosis medications. Cell Signal 2013; 25: 1272-8.

[133] Schiebler M, Brown K, Hegyi K, Newton SM, Renna M, Hepburn L, et al. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion. EMBO Mol Med 2015; 7: 127-39.

[134] Lopez-Alonso I, Aguirre A, Gonzalez-Lopez A, Fernandez AF, Amado-Rodriguez L, Astudillo A, et al. Impairment of autophagy decreases ventilator-induced lung injury by blockade of the NF-kappaB pathway. Am J Physiol Lung Cell Mol Physiol 2013; 304: L844-52.

[135] Pham DL, Kim SH, Losol P, Yang EM, Shin YS, Ye YM, et al. Association of autophagy related gene polymorphisms with neutrophilic airway inflammation in adult asthma. Korean J Intern Med 2016; 31: 375-85.

[136] Pham DL, Ban GY, Kim SH, Shin YS, Ye YM, Chwae YJ, et al. Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma. Clin Exp Allergy 2017; 47: 57-70.

[137] Racanelli AC, Kikkers SA, Choi AMK, Cloonan SM. Autophagy and inflammation in chronic respiratory disease. Autophagy 2018; 14: 221-32.

[138] Abdel Fattah E, Bhattacharya A, Herron A, Safdar Z, Eissa NT. Critical role for IL-18 in spontaneous lung inflammation caused by autophagy deficiency. J Immunol 2015; 194: 5407-16.

[139] Pietrocola F, Demont Y, Castoldi F, Enot D, Durand S, Semeraro M, et al. Metabolic effects of fasting on human and mouse blood in vivo. Autophagy 2017; 13: 567-78.

[140] Gutierrez A, Scharl M, Sempere L, Holler E, Zapater P, Almenta I, et al. Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn’s disease. Gut 2014; 63: 272-80.