Targeting macrophage autophagy for inflammation resolution and tissue repair in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic, non-specific, recurrent inflammatory disease, majorly affecting the gastrointestinal tract. Due to its unclear pathogenesis, the current therapeutic strategy for IBD is focused on symptoms alleviation. Autophagy is a lysosome-mediated catabolic process for maintaining cellular homeostasis. Genome-wide association studies and subsequent functional studies have highlighted the critical role of autophagy in IBD via a number of mechanisms, including modulating macrophage function. Macrophages are the gatekeepers of intestinal immune homeostasis, especially involved in regulating inflammation remission and tissue repair. Interestingly, many autophagic proteins and IBD-related genes have been revealed to regulate macrophage function, suggesting that macrophage autophagy is a potentially important process implicated in IBD regulation. Here, we have summarized current understanding of macrophage autophagy function in pathogen and apoptotic cell clearance, inflammation remission and tissue repair regulation in IBD, and discuss how this knowledge can be used as a strategy for IBD treatment.

Keywords

Autophagy / Inflammatory bowel diseases / Inflammation / Tissue repair / Efferocytosis / Macrophage

References

[1] Carrière J, Darfeuille-Michaud A, Nguyen HTT. Infectious etiopathogenesis of Crohn’s disease. World J Gastroenterol WJG. 2014; 20: 12102.

[2] M’koma AE. Inflammatory bowel disease: an expanding global health problem. Clin Med Insights Gastroenterol SAGE Publications Sage UK: London, England. 2013; 6:CGast-S12731.

[3] Uhlig HH, Charbit-Henrion F, Kotlarz D, Shouval DS, Schwerd T, Strisciuglio C, et al. Clinical genomics for the diagnosis of monogenic forms of inflammatory bowel disease: a position paper from the paediatric IBD Porto Group of European Society of paediatric gastroenterology, Hepatology and nutrition. J Pediatr Gastroenterol Nutr. 2021; 72: 456.

[4] Cushing K, Higgins PDR. Management of Crohn disease: a review. JAMA. 2021; 325: 69-80.

[5] Nash P, Kerschbaumer A, Dörner T, Dougados M, Fleischmann RM, Geissler K, et al. Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: A consensus statement. Ann Rheum Dis; 2021; 80: 71-87.

[6] Owczarek D, Rodacki T, Domagała-Rodacka R, Cibor D, Mach T. Diet and nutritional factors in inflammatory bowel diseases. World J Gastroenterol. 2016; 22: 895.

[7] Lloyd-Price J, Arze C, Ananthakrishnan AN, Schirmer M, Avila-Pacheco J, Poon TW, et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature. 2019; 569: 655-62.

[8] Bushman FD, Conrad M, Ren Y, Zhao C, Gu C, Petucci C, et al. Multi-omic analysis of the interaction between Clostridioides difficile infection and pediatric inflammatory bowel disease. Cell Host Microbe. 2020; 28: 422-33.

[9] Ryan FJ, Ahern AM, Fitzgerald RS, Laserna-Mendieta EJ, Power EM, Clooney AG, et al. Colonic microbiota is associated with inflammation and host epigenomic alterations in inflammatory bowel disease. Nat Commun. 2020; 11: 1-12.

[10] Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011; 474: 298-306.

[11] Liu T-C, Stappenbeck TS. Genetics and pathogenesis of inflammatory bowel disease. Annu Rev Pathol Mech Dis. 2016; 11: 127-48.

[12] Nguyen HTT, Lapaquette P, Bringer M-A, Darfeuille-Michaud A. Autophagy and Crohn’s disease. Journal of Innate Immunity. 2013; 5: 434-43.

[13] Wu MY, Liu L, Wang EJ, Xiao HT, Cai CZ, Wang J, et al. PI3KC3 complex subunit NRBF2 is required for apoptotic cell clearance to restrict intestinal inflammation. Autophagy [Internet]. 2020; 0:1Available from:. https://doi.org/10.1080/15548627.2020.1741332.

[14] Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007; 39: 207-11.

[15] Larabi A, Barnich N, Nguyen HTT. New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD. Autophagy. 2020; 16: 38-51.

[16] Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol. 2020; 877: 173090.

[17] Bain CC, Bravo-Blas A, Scott CL, Perdiguero EG, Geissmann F, Henri S, et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol. 2014; 15: 929-37.

[18] Mowat AM, Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol. 2014; 14: 667-85.

[19] Turner JR.Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009; 9: 799-809.

[20] Bogunovic M, Ginhoux F, Helft J, Shang L, Hashimoto D, Greter M, et al. Origin of the lamina propria dendritic cell network. Immunity. 2009; 31: 513-25.

[21] Bain CC, Scott CL, Uronen-Hansson H, Gudjonsson S, Jansson O, Grip O, et al. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors. Mucosal Immunol. 2013; 6: 498-510.

[22] Wang S-L, Shao B-Z, Zhao S-B, Chang X, Wang P, Miao C-Y, et al. Intestinal autophagy links psychosocial stress with gut microbiota to promote inflammatory bowel disease. Cell Death Dis. 2019; 10: 1-17.

[23] Lee H-Y, Kim J, Quan W, Lee J-C, Kim M-S, Kim S-H, et al. Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis. Autophagy. 2016; 12: 13390-1430.

[24] Zhao S, Xia J, Wu X, Zhang L, Wang P, Wang H, et al. Deficiency in class III PI3-kinase confers postnatal lethality with IBD-like features in zebrafish. Nat Commun. 2018; 9: 1-13.

[25] Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology. 2011; 140: 1704-12.

[26] Ek WE, D’Amato M, Halfvarson J. The history of genetics in inflammatory bowel disease. Ann Gastroenterol Q Publ hell Soc Gastroenterol. the Hellenic society of. Gastroenterology. 2014; 27: 294.

[27] Molodecky NA, Soon S, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012; 142: 46-54.

[28] Hugot J-P, Chamaillard M, Zouali H, Lesage S, Cézard J-P, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001; 411: 599-603.

[29] Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001; 411: 603-6.

[30] Gammoh N. The multifaceted functions of ATG16L1 in autophagy and related processes. J Cell Sci. 2020; 133: jcs249227.

[31] Murthy A, Li Y, Peng I, Reichelt M, Katakam AK, Noubade R, et al. A Crohn’s disease variant in Atg16l1 enhances its degradation by caspase 3. Nature. 2014; 506: 456-62.

[32] Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet. 2007; 39: 830-2.

[33] Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011; 469: 323-35.

[34] Singh SB, Davis AS, Taylor GA, Deretic V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science. 2006; 313: 1438-41.

[35] Saxena A, Lopes F, Poon KKH, McKay DM. Absence of the NOD2 protein renders epithelia more susceptible to barrier dysfunction due to mitochondrial dysfunction. Am J Physiol Liver Physiol. 2017; 313: G26-38.

[36] Lassen KG, McKenzie CI, Mari M, Murano T, Begun J, Baxt LA, et al. Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk. Immunity. 2016; 44: 1392-405.

[37] Zhang HZ, Cui ZH, Cheng D, Du YY, Guo XL, Gao R, et al. RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis. Autophagy Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Natl Engn Res Ctr Nanomed, Key Lab Mol Biophys,Minist Educ, 1037th Luoyu Ave, Wuhan 430074, Peoples R China. 2021; 17: 3030-47.

[38] Ranjan K, Hedl M, Abraham C. The E3 ubiquitin ligase RNF186 and RNF186 risk variants regulate innate receptor-induced outcomes. Proc Natl Acad Sci. 2021; 118:e2013500118.

[39] Homer CR, Richmond AL, Rebert NA, Achkar J, McDonald C. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology. 2010; 139: 1630-41.

[40] Levin AD, Koelink PJ, Bloemendaal FM, Vos ACW, D’Haens GR, van den Brink GR, et al. Autophagy contributes to the induction of anti-TNF induced macrophages. J Crohn’s Colitis. 2016; 10: 323-9.

[41] Gao P, Liu H, Huang H, Sun Y, Jia B, Hou B, et al. The Crohn disease-associated ATG16L1T300A polymorphism regulates inflammatory responses by modulating TLR-and NLR-mediated signaling. Autophagy. 2022; 18: 2561-75.

[42] Saitoh T, Fujita N, Jang MH, Uematsu S, Yang B-G, Satoh T, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-β production. Nature. 2008; 456: 264-8.

[43] Zhang H, Zheng L, McGovern DPB, Hamill AM, Ichikawa R, Kanazawa Y, et al. Myeloid ATG16L1 facilitates host-bacteria interactions in maintaining intestinal homeostasis. J Immunol. 2017; 198: 2133-46.

[44] Buisson A, Douadi C, Ouchchane L, Goutte M, Hugot J-P, Dubois A, et al. Macrophages inability to mediate adherent-invasive E. coli replication is linked to autophagy in Crohn’s disease patients. Cell. 2019; 8: 1394.

[45] Schwerd T, Pandey S, Yang H-T, Bagola K, Jameson E, Jung J, et al. Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn’s disease. Gut. 2017; 66: 1060-73.

[46] Smith AM, Sewell GW, Levine AP, Chew TS, Dunne J, O’Shea NR, et al. Disruption of macrophage pro-inflammatory cytokine release in Crohn’s disease is associated with reduced optineurin expression in a subset of patients. Immunology. 2015; 144: 45-55.

[47] Chew TS, O’Shea NR, Sewell GW, Oehlers SH, Mulvey CM, Crosier PS, et al. Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis. Dis Model Mech. 2015; 8: 817-29.

[48] Lahiri A, Hedl M, Abraham C. MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation. Proc Natl Acad Sci. 2015; 112: 10461-6.

[49] Lee JPW, Foote A, Fan H, Peral de Castro C, Lang T, Jones SA, et al. Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages. Autophagy. 2016; 12: 907-16.

[50] Xia Y, Liu N, Xie X, Bi G, Ba H, Li L, et al. The macrophage-specific V-ATPase subunit ATP6V0D2 restricts inflammasome activation and bacterial infection by facilitating autophagosome-lysosome fusion. Autophagy. 2019; 15: 960-75.

[51] Barker N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol. 2014; 15: 19-33.

[52] Zheng Y, Yu Y, Chen X-F, Yang S-L, Tang X-L, Xiang Z-G. Intestinal macrophage autophagy and its pharmacological application in inflammatory bowel disease. Front Pharmacol. 2021; 12: 803686.

[53] van Furth R, Cohn ZA, Hirsch JG, Humphrey JH, Spector WG, Langevoort H. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull World Health Organ. 1972; 46: 845.

[54] Cummings RJ, Barbet G, Bongers G, Hartmann BM, Gettler K, Muniz L, et al. Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature. 2016; 539: 565-9.

[55] Poon IKH, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014; 14: 166-80.

[56] Qualls JE, Kaplan AM, Van Rooijen N, Cohen DA. Suppression of experimental colitis by intestinal mononuclear phagocytes. J Leukoc Biol. 2006; 80: 802-15.

[57] Hume DA, Perry VH, Gordon S. The mononuclear phagocyte system of the mouse defined by immunohistochemical localisation of antigen F4/80: macrophages associated with epithelia. Anat Rec. 1984; 210: 503-12.

[58] Bain CC, Mowat AM. Macrophages in intestinal homeostasis and inflammation. Immunol Rev. 2014; 260: 102-17.

[59] Seyedizade SS, Afshari K, Bayat S, Rahmani F, Momtaz S, Rezaei N, et al. Current status of M1 and M2 macrophages pathway as drug targets for inflammatory bowel disease. Arch Immunol Ther Exp. 2020; 68: 1-24.

[60] Zhu W, Yu J, Nie Y, Shi X, Liu Y, Li F, et al. Disequilibrium of M1 and M2 macrophages correlates with the development of experimental inflammatory bowel diseases. Immunol Investig. 2014; 43: 638-52.

[61] Kühl AA, Erben U, Kredel LI, Siegmund B. Diversity of intestinal macrophages in inflammatory bowel diseases. Front Immunol. 2015; 6: 613.

[62] Du Y, Rong L, Cong Y, Shen L, Zhang N, Wang B. Macrophage polarization: an effective approach to targeted therapy of inflammatory bowel disease. Expert Opin Ther Targets. 2021; 25: 191-209.

[63] Hidalgo-Garcia L, Galvez J, Rodriguez-Cabezas ME, Anderson PO. Can a conversation between mesenchymal stromal cells and macrophages solve the crisis in the inflamed intestine? Front Pharmacol. 2018; 9: 179.

[64] Abraham C, Medzhitov R. Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology. 2011; 140: 1729-37.

[65] Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing γ δ T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009; 31: 321-30.

[66] Zigmond E, Varol C, Farache J, Elmaliah E, Satpathy AT, Friedlander G, et al. Ly6Chi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity. 2012; 37: 1076-90.

[67] Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, et al. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science. 2017; 356: 1072-6.

[68] Lee C, Penberthy K, Wheeler K, Juncadella I, Vandenabeele P, Lysiak J, et al. Boosting apoptotic cell clearance by colonic epithelial cells attenuates inflammation in vivo. Immunity. 2016; S1074761316300206.

[69] A-Gonzalez N, Quintana JA, García-Silva S, Mazariegos M, González de la Aleja A, Nicolás-Ávila JA, et al. Phagocytosis imprints heterogeneity in tissue-resident macrophages. J Exp Med. 2017; 214: 1281-96.

[70] Noelia A, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009; 31: 245-58.

[71] Lin S-L, Li B, Rao S, Yeo E-J, Hudson TE, Nowlin BT, et al. Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci. 2010; 107: 4194-9.

[72] Farin HF, Van Es JH, Clevers H. Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells. Gastroenterology. 2012; 143: 1518-29.

[73] Pull SL, Doherty JM, Mills JC, Gordon JI, Stappenbeck TS. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci. 2005; 102: 99-104.

[74] Anderson EC, Wong MH. Caught in the Akt: regulation of Wnt signaling in the intestine. Gastroenterology. 2010; 139: 718-22.

[75] Mowat AM, Bain CC. Mucosal macrophages in intestinal homeostasis and inflammation. Journal of Innate Immunity. 2011; 3: 550-64.

[76] D’Angelo F, Bernasconi E, Schäfer M, Moyat M, Michetti P, Maillard MH, et al. Macrophages promote epithelial repair through hepatocyte growth factor secretion. Clin Exp Immunol. 2013; 174: 60-72.

[77] Ortiz-Masia D, Cosin-Roger J, Calatayud S, Hernandez C, Alos R, Hinojosa J, et al. Hypoxic macrophages impair autophagy in epithelial cells through Wnt1: relevance in IBD. Mucosal Immunol. 2014; 7: 929-38.

[78] Talero E, Garcia-Maurino S, Motilva V. Melatonin, autophagy and intestinal bowel disease. Curr Pharm Des. 2014; 20: 4816-27.

[79] Travassos LH, Carneiro LAM, Ramjeet M, Hussey S, Kim Y-G, Magalhães JG, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010; 11: 55-62.

[80] Lapaquette P, Glasser A, Huett A, Xavier RJ, Darfeuille-Michaud A. Crohn’s disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell Microbiol. 2010; 12: 99-113.

[81] Strisciuglio C, Duijvestein M, Verhaar AP, Vos ACW, den Brink GR, Hommes DW, et al. Impaired autophagy leads to abnormal dendritic cell-epithelial cell interactions. J Crohn’s Colitis. 2013; 7: 534-41.

[82] Ogawa M, Yoshikawa Y, Kobayashi T, Mimuro H, Fukumatsu M, Kiga K, et al. A Tecpr1-dependent selective autophagy pathway targets bacterial pathogens. Cell Host Microbe. 2011; 9: 376-89.

[83] Cemma M, Kim PK, Brumell JH. The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target salmonella to the autophagy pathway. Autophagy. 2011; 7: 341-5.

[84] Randow F. How cells deploy ubiquitin and autophagy to defend their cytosol from bacterial invasion. Autophagy. 2011; 7: 304-9.

[85] Manichanh C, Rigottier-Gois L, Bonnaud E, Gloux K, Pelletier E, Frangeul L, et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut. 2006; 55: 205-11.

[86] Martinez-Medina M, Aldeguer X, Lopez-Siles M, González-Huix F, López-Oliu C, Dahbi G, et al. Molecular diversity of Escherichia coli in the human gut: new ecological evidence supporting the role of adherent-invasive E. coli (AIEC) in Crohn’s disease. Inflamm Bowel Dis. 2009; 15: 872-82.

[87] Rolhion N, Darfeuille-Michaud A. Adherent-invasive Escherichia coli in inflammatory bowel disease. Inflamm Bowel Dis. 2007; 13: 1277-83.

[88] Caprilli R, Lapaquette P, Darfeuille-Michaud A. Eating the enemy in Crohn’s disease: an old theory revisited. J Crohn’s Colitis. 2010; 4: 377-83.

[89] Darfeuille-Michaud A. Adherent-invasive Escherichia coli: a putative new E. coli pathotype associated with Crohn’s disease. International Journal of Medical Microbiology. 2002; 292: 185-93.

[90] Glasser A-L, Boudeau J, Barnich N, Perruchot M-H, Colombel J-F, Darfeuille-Michaud A. Adherent invasive Escherichia coli strains from patients with Crohn’s disease survive and replicate within macrophages without inducing host cell death. Infect Immun. 2001; 69: 5529-37.

[91] Palmela C, Chevarin C, Xu Z, Torres J, Sevrin G, Hirten R, et al. Adherent-invasive Escherichia coli in inflammatory bowel disease. Gut. 2018; 67: 574-87.

[92] Sun R, Abraham C. IL23 promotes antimicrobial pathways in human macrophages, which are reduced with the IBD-protective IL23R R381Q variant. Cellular and Molecular Gastroenterology and Hepatology. 2020; 10: 673-97.

[93] Shi C-S, Kehrl JH. MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J Biol Chem. 2008; 283: 33175-82.

[94] Xu YI, Jagannath C, Liu X-D, Sharafkhaneh A, Kolodziejska KE, Eissa NT. Toll-like receptor 4 is a sensor for autophagy associated with innate immunity. Immunity. 2007; 27: 135-44.

[95] Krause K, Caution K, Badr A, Hamilton K, Saleh A, Patel K, et al. CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection. Autophagy. 2018; 14: 1928-42.

[96] Abdolmaleki F, Farahani N, Gheibi Hayat SM, Pirro M, Bianconi V, Barreto GE, et al. The role of efferocytosis in autoimmune diseases. Front Immunol. 2018; 9: 1645.

[97] Morioka S, Maueröder C, Ravichandran KS. Living on the edge: Efferocytosis at the interface of homeostasis and pathology. Immunity. 2019; 50: 1149-62.

[98] Angsana J, Chen J, Liu L, Haller CA, Chaikof EL. Efferocytosis as a regulator of macrophage chemokine receptor expression and polarization. Eur J Immunol. 2016; 46: 1592-9.

[99] Mehrotra P, Ravichandran KS. Drugging the efferocytosis process: concepts and opportunities. Nat Rev Drug Discov. 2022; 21: 601-20.

[100] Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol. 2010; 6: 280-9.

[101] Korns D, Frasch SC, Fernandez-Boyanapalli R, Henson PM, Bratton DL. Modulation of macrophage efferocytosis in inflammation. Front Immunol. 2011; 2: 57.

[102] Martin-Rodriguez O, Gauthier T, Bonnefoy F, Couturier M, Daoui A, Chagué C, et al. Pro-resolving factors released by macrophages after Efferocytosis promote mucosal wound healing in inflammatory bowel disease. Front Immunol. 2021; 12: 754475.

[103] Heckmann BL, Green DR. LC3-associated phagocytosis at a glance. J Cell Sci. 2019; 132: 0-2.

[104] Liu B, Zhang B, Guo R, Li S, Xu Y. Enhancement in efferocytosis of oxidized low-density lipoprotein-induced apoptotic RAW264. 7 cells through Sirt1-mediated autophagy. Int J Mol Med. 2014; 33: 523- 33.

[105] Ouimet M, Ediriweera H, Afonso MS, Ramkhelawon B, Singaravelu R, Liao X, et al. microRNA-33 regulates macrophage autophagy in atherosclerosis. Arterioscler Thromb Vasc Biol. 2017; 37: 1058-67.

[106] Wang Z, Sequeira RC, Zabalawi M, Madenspacher J, Boudyguina E, Ou T, et al. Myeloid atg5 deletion impairs n-3 PUFA-mediated atheroprotection. Atherosclerosis. 2020; 295: 8-17.

[107] Tartakover Matalon S, Ringel Y, Konikoff F, Drucker L, Pery S, Naftali T. Cannabinoid receptor 2 agonist promotes parameters implicated in mucosal healing in patients with inflammatory bowel disease. United Eur Gastroenterol J. SAGE Publications Sage UK: London, England; 2020; 8: 271-83.

[108] Lin X, Zheng X, Fan D, Yao Q, Hu J, Lian L, et al. MicroRNA-143 targets ATG2B to inhibit autophagy and increase inflammatory responses in Crohn’s disease. Inflamm Bowel Dis. 2018; 24: 781-91.

[109] Wang Z, Shi L, Hua S, Qi C, Fang M. IL-33 ameliorates experimental colitis involving regulation of autophagy of macrophages in mice. Cell & Bioscience. 2019; 9: 1-9.

[110] López-Peláez M, Soria-Castro I, Boscá L, Fernández M, Alemany S. Cot/tpl2 activity is required for TLR-induced activation of the Akt p70 S6k pathway in macrophages: implications for NO synthase 2 expression. Eur J Immunol. 2011; 41: 1733- 41.

[111] Liu R, Li X, Ma H, Yang Q, Shang Q, Song L, et al. Spermidine endows macrophages anti-inflammatory properties by inducing mitochondrial superoxide-dependent AMPK activation, Hif-α upregulation and autophagy. Free Radic Biol Med. 2020; 161: 339-50.

[112] Chuang S-Y, Yang C-H, Chou C-C, Chiang Y-P, Chuang T-H, Hsu L-C. TLR-induced PAI-2 expression suppresses IL-β processing via increasing autophagy and NLRP3 degradation. Proc Natl Acad Sci. 2013; 110: 16079-84.

[113] Spalinger MR, Lang S, Gottier C, Dai X, Rawlings DJ, Chan AC, et al. PTPN22 regulates NLRP3-mediated IL1B secretion in an autophagy-dependent manner. Autophagy. 2017; 13: 1590-601.

[114] Nakahira K, Haspel JA, Rathinam VAK, Lee S-J, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011; 12: 222-30.

[115] Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017; 356: 513-9.

[116] Yan J, Hedl M, Abraham C. An inflammatory bowel disease-risk variant in INAVA decreases pattern recognition receptor-induced outcomes. J Clin Invest. 2017; 127: 2192-205.

[117] Sun R, Hedl M, Abraham C. TNFSF15 promotes antimicrobial pathways in human macrophages and these are modulated by TNFSF15 disease-risk variants. Cellular and Molecular Gastroenterology and Hepatology. 2021; 11: 249-72.

[118] Moparthi L, Koch S. Wnt signaling in intestinal inflammation. Differentiation. 2019; 108: 24-32.

[119] Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014; 15: 155-62.

[120] Zheng X, Wang S, Xiao L, Han P, Xie K, Ivanovski S, et al. LiCl-induced immunomodulatory periodontal regeneration via the activation of the Wnt/-catenin signaling pathway. J Periodontal Res. 2022; 57: 835-48.

[121] Chen L, Yang Y, Bao J, Wang Z, Xia M, Dai A, et al. Autophagy negative-regulating Wnt signaling enhanced inflammatory osteoclastogenesis from pre-OCs in vitro. Biomed Pharmacother. 2020; 126: 110093.

[122] Naskar D, Maiti G, Chakraborty A, Roy A, Chattopadhyay D, Sen M. Wnt5a-Rac1-NF-κB homeostatic circuitry sustains innate immune functions in macrophages. J Immunol. 2014; 192: 4386-97.

[123] Jati S, Kundu S, Chakraborty A, Mahata SK, Nizet V, Sen M. Wnt5A signaling promotes defense against bacterial pathogens by activating a host autophagy circuit. Front Immunol. 2018; 9: 679.

[124] Gao Y, Wen Q, Hu S, Zhou X, Xiong W, Du X, et al. IL-36γ promotes killing of mycobacterium tuberculosis by macrophages via WNT5A-induced noncanonical WNT signaling. J Immunol. 2019; 203: 922-35.

[125] Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014; 146: 96-109.

[126] Prins MM, Verstockt B, Ferrante M, Vermeire S, Wildenberg ME, Koelink PJ. Monocyte TREM-1 levels associate with anti-TNF responsiveness in IBD through autophagy and Fcγ-receptor Signaling pathways. Front Immunol. 2021; 12: 627535.

[127] Guo W, Sun Y, Liu W, Wu X, Guo L, Cai P, et al. Small molecule-driven mitophagy-mediated NLRP3 inflammasome inhibition is responsible for the prevention of colitis-associated cancer. Autophagy. 2014; 10: 972-85.

[128] Shao B, Wei W, Ke P, Xu Z, Zhou J, Liu C. Activating cannabinoid receptor 2 alleviates pathogenesis of experimental autoimmune encephalomyelitis via activation of autophagy and inhibiting NLRP 3 inflammasome. CNS Neuroscience & Therapeutics. 2014; 20: 1021-8.

[129] Thachil É, Hugot J, Arbeille B, Paris R, Grodet A, Peuch-maur M, et al. Abnormal activation of autophagy-induced crinophagy in Paneth cells from patients with Crohn’s disease. Gastroenterology. 2012; 142: 1097-9.

[130] Wlodarska M, Thaiss CA, Nowarski R, Henao-Mejia J, Zhang J-P, Brown EM, et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell. 2014; 156: 1045-59.

[131] Cosin-Roger J, Simmen S, Melhem H, Atrott K, Frey-Wagner I, Hausmann M, et al. Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Nat Commun. 2017; 8: 1-13.

[132] Shen T, Li S, Cai L-D, Liu J-L, Wang C-Y, Gan W-J, et al. Erbin exerts a protective effect against inflammatory bowel disease by suppressing autophagic cell death. Oncotarget. 2018; 9: 12035.

[133] Zhao S-B, Wu J-Y, He Z-X, Song Y-H, Chang X, Xia T, et al. Corticotropin releasing hormone promotes inflammatory bowel disease via inducing intestinal macrophage autophagy. Cell death Discov. 2021; 7: 1-13.

[134] Denton D, Kumar S. Autophagy-dependent cell death. Cell Death Differ. 2019; 26: 605-16.

[135] Baxt LA, Xavier RJ. Role of autophagy in the maintenance of intestinal homeostasis. Gastroenterology. 2015; 149: 553-62.

[136] Foerster EG, Mukherjee T, Cabral-Fernandes L, Rocha JDB, Girardin SE, Philpott DJ. How autophagy controls the intestinal epithelial barrier. Autophagy. 2022; 18: 86-103.