250
Views
0
CrossRef citations to date
0
Altmetric
Review

Macrophages-microenvironment crosstalk in fibrostenotic inflammatory bowel disease: from basic mechanisms to clinical applications

ORCID Icon, , ORCID Icon, ORCID Icon, , , ORCID Icon & ORCID Icon show all
Pages 1011-1026 | Received 04 Jul 2022, Accepted 20 Dec 2022, Published online: 27 Dec 2022

References

  • Pakshir P, Hinz B. The big five in fibrosis: macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 2018 Aug;68–69:81–93. DOI:10.1016/j.matbio.2018.01.019
  • Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020;587(7835):555–566.
  • Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis. 2002 Jul;8(4):244–250.
  • Gordon IO, Agrawal N, Willis E, et al. Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation. Aliment Pharmacol Ther. 2018 Apr;47(7):922–939.
  • D’Alessio S, Ungaro F, Noviello D, et al. Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat Rev Gastroenterol Hepatol. 2022 Mar;19(3):169–184.
  • Schulberg JD, Wright EK, Holt BA, et al. Intensive drug therapy versus standard drug therapy for symptomatic intestinal Crohn’s disease strictures (STRIDENT): an open-label, single-centre, randomised controlled trial. Lancet Gastroenterol Hepatol. 2022 Apr;7(4):318–331.
  • Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016 Jun;12(6):325–338.
  • Di Mola FF, Friess H, Scheuren A, et al. Transforming growth factor-betas and their signaling receptors are coexpressed in Crohn’s disease. Ann Surg. 1999 Jan;229(1):67–75.
  • De Schepper S, Verheijden S, Aguilera-Lizarraga J, et al. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell. 2018 Oct 4;175(2):400–415 e13.
  • Graf T, Enver T. Forcing cells to change lineages. Nature. 2009;462(7273):587–594.
  • Martin P, D’Souza D, Martin J, et al. Wound healing in the PU.1 null mouse–tissue repair is not dependent on inflammatory cells. Curr Biol. 2003 Jul 1;13(13):1122–1128.
  • Kuroda N, Masuya M, Tawara I, et al. Infiltrating CCR2(+) monocytes and their progenies, fibrocytes, contribute to colon fibrosis by inhibiting collagen degradation through the production of TIMP-1. Sci Rep. 2019 Jun 12;9(1):8568.
  • Schleier L, Wiendl M, Heidbreder K, et al. Non-classical monocyte homing to the gut via α4β7 integrin mediates macrophage-dependent intestinal wound healing. Gut. 2020 Feb;69(2):252–263.
  • Patel AA, Zhang Y, Fullerton JN, et al. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med. 2017 Jul 3;214(7):1913–1923.
  • Viola MF, Boeckxstaens G. Niche-specific functional heterogeneity of intestinal resident macrophages. Gut. 2021 Jul;70(7):1383–1395.
  • Bujko A, Atlasy N, Landsverk OJB, et al. Transcriptional and functional profiling defines human small intestinal macrophage subsets. J Exp Med. 2018 Feb 5;215(2):441–458.
  • Shapouri-Moghaddam A, Mohammadian S, Vazini H, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018 Sep;233(9):6425–6440.
  • Xue J, Schmidt SV, Sander J, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity. 2014 Feb 20;40(2):274–288.
  • Chavez-Galan L, Olleros ML, Vesin D, et al. Much more than M1 and M2 macrophages, there are also CD169(+) and TCR(+) macrophages. Front Immunol. 2015;6:263.
  • Li C, Iness A, Yoon J, et al. Noncanonical STAT3 activation regulates excess TGF-β1 and collagen I expression in muscle of stricturing Crohn’s disease. J Immunol. 2015 Apr 1;194(7):3422–3431.
  • Tait Wojno ED, Hunter CA, Stumhofer JS. The immunobiology of the interleukin-12 family: room for discovery. Immunity. 2019 Apr 16;50(4):851–870.
  • Murate K, Nakamura M, Fujishiro M. A case where administration of ustekinumab maintained the intestinal patency after balloon dilation for small intestinal stenosis caused by crohn’s disease. Inflamm Bowel Dis. 2019 Oct 18;25(11):e140.
  • Mathur R, Alam MM, Zhao XF, et al. Induction of autophagy in Cx3cr1(+) mononuclear cells limits IL-23/IL-22 axis-mediated intestinal fibrosis. Mucosal Immunol. 2019 May;12(3):612–623.
  • Postlethwaite AE, Raghow R, Stricklin GP, et al. Modulation of fibroblast functions by interleukin 1: increased steady-state accumulation of type I procollagen messenger RNAs and stimulation of other functions but not chemotaxis by human recombinant interleukin 1 alpha and beta. J Cell Biol. 1988 Feb;106(2):311–318.
  • Otto G. IL-1β switches on kidney fibrosis. Nat Rev Nephrol. 2018;14(8):475.
  • Reiter FP, Wimmer R, Wottke L, et al. Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4(-/-) mouse model. World J Hepatol. 2016 Mar 18;8(8):401–410.
  • Latella G, Rogler G, Bamias G, et al. Results of the 4th scientific workshop of the ECCO (I): pathophysiology of intestinal fibrosis in IBD. J Crohn’s Colitis. 2014;8(10):1147–1165.
  • Okuno T, Andoh A, Bamba S, et al. Interleukin-1beta and tumor necrosis factor-alpha induce chemokine and matrix metalloproteinase gene expression in human colonic subepithelial myofibroblasts. Scand J Gastroenterol. 2002 Mar;37(3):317–324.
  • Graham MF, Willey A, Adams J, et al. Interleukin 1 beta down-regulates collagen and augments collagenase expression in human intestinal smooth muscle cells. Gastroenterology. 1996 Feb;110(2):344–350.
  • Hügle B, Speth F, Haas JP. Inflammatory bowel disease following anti-interleukin-1-treatment in systemic juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2017 Mar 14;15(1):16.
  • Nishida A, Inatomi O, Fujimoto T, et al. Interleukin-36α induces inflammatory mediators from human pancreatic myofibroblasts via a myd88 dependent pathway. Pancreas. 2017 Apr;46(4):539–548.
  • Scheibe K, Kersten C, Schmied A, et al. Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation. Gastroenterology. 2019 Mar;156(4):1082–1097.e11.
  • Medina-Contreras O, Harusato A, Nishio H, et al. Cutting edge: IL-36 receptor promotes resolution of intestinal damage. J Immunol. 2016 Jan 1;196(1):34–38.
  • Kotsiou OS, Gourgoulianis KI, Zarogiannis SG. IL-33/ST2 axis in organ fibrosis. Front Immunol. 2018;9:2432.
  • Lee JS, Seppanen E, Patel J, et al. ST2 receptor invalidation maintains wound inflammation, delays healing and increases fibrosis. Exp Dermatol. 2016;25(1):71–74.
  • Masterson JC, Capocelli KE, Hosford L, et al. Eosinophils and IL-33 perpetuate chronic inflammation and fibrosis in a pediatric population with stricturing crohn’s ileitis. Inflamm Bowel Dis. 2015;21(10):2429–2440.
  • Zhang ZZ, Zhang Y, He T, et al. Homozygous IL37 mutation associated with infantile inflammatory bowel disease. Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). DOI:10.1073/pnas.2009217118.
  • Franzè E, Dinallo V, Laudisi F, et al. Interleukin-34 stimulates gut fibroblasts to produce collagen synthesis. J Crohn’s Colitis. 2020;14(10):1436–1445.
  • Otsuka R, Wada H, K-i S. IL-34, the rationale for its expression in physiological and pathological conditions. Semin Immunol. 2021;54:101517.
  • Honzawa Y, Nakase H, Shiokawa M, et al. Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn’s disease. Gut. 2014 Dec;63(12):1902–1912.
  • Biancheri P, Pender SL, Ammoscato F, et al. The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis. Fibrogenesis Tissue Repair. 2013 Jul 8;6(1):13.
  • Sommerfeld SD, Cherry C, Schwab RM, et al. Interleukin-36γ-producing macrophages drive IL-17-mediated fibrosis. Sci Immunol. 2019 Oct 11;4(40). DOI:10.1126/sciimmunol.aax4783.
  • Zhang HJ, Zhang YN, Zhou H, et al. IL-17A promotes initiation and development of intestinal fibrosis through EMT. Dig Dis Sci. 2018 Nov;63(11):2898–2909.
  • Magdaleno-Tapial J, López-Martí C, Ortiz-Salvador JM, et al. Can secukinumab improve liver fibrosis? A pilot prospective study of 10 psoriatic patients. Dermatol Ther. 2021;34(5):e15065.
  • Szanto A, Balint BL, Nagy ZS, et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPARγ-regulated gene expression in macrophages and dendritic cells. Immunity. 2010 Nov 24;33(5):699–712.
  • Pello OM, De Pizzol M, Mirolo M, et al. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood. 2012;119(2):411–421.
  • Ebrahimi Daryani N, Saghazadeh A, Moossavi S, et al. Interleukin-4 and Interleukin-10 Gene Polymorphisms in Patients with Inflammatory Bowel Disease. Immunol Invest. 2017 Oct;46(7):714–729.
  • Schreiber S, Heinig T, Panzer U, et al. Impaired response of activated mononuclear phagocytes to interleukin 4 in inflammatory bowel disease. Gastroenterology. 1995 Jan;108(1):21–33.
  • Jayme TS, Leung G, Wang A, et al. Human interleukin-4-treated regulatory macrophages promote epithelial wound healing and reduce colitis in a mouse model. Sci Adv. 2020;6(23):eaba4376–eaba4376.
  • Fichtner-Feigl S, Strober W, Kawakami K, et al. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med. 2006 Jan;12(1):99–106.
  • Fichtner-Feigl S, Young CA, Kitani A, et al. IL-13 signaling via IL-13R alpha2 induces major downstream fibrogenic factors mediating fibrosis in chronic TNBS colitis. Gastroenterology. 2008 Dec;135(6):2003–2013. 2013.e1-7.
  • Li P, Liang ML, Zhu Y, et al. Resveratrol inhibits collagen I synthesis by suppressing IGF-1R activation in intestinal fibroblasts. World J Gastroenterol. 2014 Apr 28;20(16):4648–4661.
  • Fruchtman S, Simmons JG, Michaylira CZ, et al. Suppressor of cytokine signaling-2 modulates the fibrogenic actions of GH and IGF-I in intestinal mesenchymal cells. Am J Physiol Gastrointest Liver Physiol. 2005 Aug;289(2):G342–50.
  • Xin X, Hou YT, Li L, et al. IGF-I increases IGFBP-5 and collagen alpha1(I) mRNAs by the MAPK pathway in rat intestinal smooth muscle cells. Am J Physiol Gastrointest Liver Physiol. 2004 May;286(5):G777–83.
  • Theiss AL, Fruchtman S, Lund PK. Growth factors in inflammatory bowel disease: the actions and interactions of growth hormone and insulin-like growth factor-I. Inflamm Bowel Dis. 2004 Nov;10(6):871–880.
  • Simmons JG, Pucilowska JB, Keku TO, et al. IGF-I and TGF-beta1 have distinct effects on phenotype and proliferation of intestinal fibroblasts. Am J Physiol Gastrointest Liver Physiol. 2002 Sep;283(3):G809–18.
  • Lawrance IC, Maxwell L, Doe W. Altered response of intestinal mucosal fibroblasts to profibrogenic cytokines in inflammatory bowel disease. Inflamm Bowel Dis. 2001 Aug;7(3):226–236.
  • Raghu G, Richeldi L, Crestani B, et al. SAR156597 in idiopathic pulmonary fibrosis: a phase 2 placebo-controlled study (DRI11772). Eur Respir J. 2018 Dec;52(6):1801130.
  • Allanore Y, Wung P, Soubrane C, et al. A randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2020 Dec;79(12):1600–1607.
  • Ouyang W, Rutz S, Crellin NK, et al. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol. 2011;29(1):71–109.
  • Koelink PJ, Bloemendaal FM, Li B, et al. Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling. Gut. 2020 Jun;69(6):1053–1063.
  • Correa I, Veny M, Esteller M, et al. Defective IL-10 production in severe phenotypes of Crohn’s disease. J Leukoc Biol. 2009 May;85(5):896–903.
  • Buruiana FE, Solà I, Alonso-Coello P. Recombinant human interleukin 10 for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2010 Nov 10;2010(11):Cd005109.
  • Reitamo S, Remitz A, Tamai K, et al. Interleukin-10 modulates type I collagen and matrix metalloprotease gene expression in cultured human skin fibroblasts. J Clin Invest. 1994 Dec;94(6):2489–2492.
  • Shi MN, Huang YH, Zheng WD, et al. Relationship between transforming growth factor beta1 and anti-fibrotic effect of interleukin-10. World J Gastroenterol. 2006 Apr 21;12(15):2357–2362.
  • Hulsmans M, Sager HB, Roh JD, et al. Cardiac macrophages promote diastolic dysfunction. J Exp Med. 2018 Feb 5;215(2):423–440.
  • Zigmond E, Bernshtein B, Friedlander G, et al. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity. 2014;40(5):720–733.
  • D’Haens G, Rieder F, Feagan BG, et al. Challenges in the pathophysiology, diagnosis, and management of intestinal fibrosis in inflammatory bowel disease. Gastroenterology. 2022 Jan;162(1):26–31.
  • D’Haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab anti–tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology. 1999;116(5):1029–1034.
  • Kugathasan S, Denson LA, Walters TD, et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet. 2017;389(10080):1710–1718.
  • Crombé V, Salleron J, Savoye G, et al. Long-term outcome of treatment with infliximab in pediatric-onset Crohn’s disease: a population-based study. Inflamm Bowel Dis. 2011 Oct;17(10):2144–2152.
  • Siegel CA, Siegel LS, Hyams JS, et al. Real-time tool to display the predicted disease course and treatment response for children with Crohn’s disease. Inflamm Bowel Dis. 2011 Jan;17(1):30–38.
  • de Bruyn JR, Becker MA, Steenkamer J, et al., Intestinal fibrosis is associated with lack of response to Infliximab therapy in Crohn’s disease. PloS one. 2018;13(1):e0190999–e0190999. .
  • Adler J, Rahal K, Swanson SD, et al. Anti-tumor necrosis factor α prevents bowel fibrosis assessed by messenger RNA, histology, and magnetization transfer MRI in rats with Crohn’s disease. Inflamm Bowel Dis. 2013 Mar-Apr;19(4):683–690.
  • Hassan-Zahraee M, Ye Z, Xi L, et al., Antitumor necrosis factor-like ligand 1A therapy targets tissue inflammation and fibrosis pathways and reduces gut pathobionts in ulcerative colitis. Inflamm Bowel Dis. 2022;28(3):434–446.
  • Ślebioda TJ, Bojarska-Junak A, Stanisławowski M, et al. TL1A as a potential local inducer of IL17A expression in colon mucosa of inflammatory bowel disease patients. Scand J Immunol. 2015 Oct;82(4):352–360.
  • Li H, Song J, Niu G, et al. TL1A blocking ameliorates intestinal fibrosis in the T cell transfer model of chronic colitis in mice. Pathol Res Pract. 2018 Feb;214(2):217–227.
  • Zhou X, Franklin RA, Adler M, et al. Circuit design features of a stable two-cell system. Cell. 2018;172(4):744–757.e17.
  • Klebl FH, Olsen JE, Jain S, et al. Expression of macrophage-colony stimulating factor in normal and inflammatory bowel disease intestine. J Pathol. 2001 Dec;195(5):609–615.
  • Li HW, Tang SL. Colony stimulating factor-1 and its receptor in gastrointestinal malignant tumors. J Cancer. 2021;12(23):7111–7119.
  • Han X, Li W, Li P, et al. Stimulation of α7 nicotinic acetylcholine receptor by nicotine suppresses decidual M1 macrophage polarization against inflammation in lipopolysaccharide-induced preeclampsia-like mouse model. Front Immunol. 2021;12:642071.
  • Wheeler KC, Jena MK, Pradhan BS, et al. VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PLoS One. 2018;13(1):e0191040.
  • Di Sabatino A, Ciccocioppo R, Armellini E, et al. Serum bFGF and VEGF correlate respectively with bowel wall thickness and intramural blood flow in Crohn’s disease. Inflamm Bowel Dis. 2004 Sep;10(5):573–577.
  • Karimi-Shah BA, Chowdhury BA. Forced vital capacity in idiopathic pulmonary fibrosis–FDA review of pirfenidone and nintedanib. N Engl J Med. 2015;372(13):1189–1191.
  • Zhang YE. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009 Jan;19(1):128–139.
  • Conery AR, Cao Y, Thompson EA, et al. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat Cell Biol. 2004 Apr;6(4):366–372.
  • Remy I, Montmarquette A, Michnick SW. PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat Cell Biol. 2004 Apr;6(4):358–365.
  • Kua HY, Liu H, Leong WF, et al. c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression. Nat Cell Biol. 2012 Jun 24;14(7):727–737.
  • Daniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest. 2004 Nov;114(9):1308–1316.
  • Dees C, Tomcik M, Palumbo-Zerr K, et al. JAK-2 as a novel mediator of the profibrotic effects of transforming growth factor β in systemic sclerosis. Arthritis Rheum. 2012 Sep;64(9):3006–3015.
  • Liu Y, Liu H, Meyer C, et al. Transforming growth factor-β (TGF-β)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation. J Biol Chem. 2013;288(42):30708–30719.
  • Wang L, Zhu Y, Sharma K. Transforming growth factor-beta1 stimulates protein kinase A in mesangial cells. J Biol Chem. 1998 Apr 3;273(14):8522–8527.
  • Zhang L, Duan CJ, Binkley C, et al. A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A. Mol Cell Biol. 2004 Mar;24(5):2169–2180.
  • McDonald OG, Wu H, Timp W, et al. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nat Struct Mol Biol. 2011 Jul 3;18(8):867–874.
  • Sadler T, Scarpa M, Rieder F, et al. Cytokine-induced chromatin modifications of the type I collagen alpha 2 gene during intestinal endothelial-to-mesenchymal transition. Inflamm Bowel Dis. 2013 Jun;19(7):1354–1364.
  • Minutti CM, Modak RV, Macdonald F, et al. A macrophage-pericyte axis directs tissue restoration via amphiregulin-induced transforming growth factor beta activation. Immunity. 2019 Mar 19;50(3):645–654.e6.
  • Arpaia N, Green Jesse A, Moltedo B, et al. A distinct function of regulatory t cells in tissue protection. Cell. 2015;162(5):1078–1089.
  • Burzyn D, Kuswanto W, Kolodin D, et al. A special population of regulatory t cells potentiates muscle repair. Cell. 2013;155(6):1282–1295.
  • Sands BE, Feagan BG, Sandborn WJ, et al. Mongersen (GED-0301) for active crohn’s disease: results of a phase 3 study. Am J Gastroenterol. 2020 May;115(5):738–745.
  • O’Neill LA, Pearce EJ. Immunometabolism governs dendritic cell and macrophage function. J Exp Med. 2016 Jan 11;213(1):15–23.
  • Geeraerts X, Bolli E, Fendt SM, et al. Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front Immunol. 2017;8:289.
  • Van den Bossche J, Baardman J, Otto NA, et al. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep. 2016 Oct 11;17(3):684–696.
  • Murray PJ, Rathmell J, Pearce E. SnapShot: immunometabolism. Cell Metab. 2015;22(1):190–190.e1.
  • Tannahill GM, Curtis AM, Adamik J, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013 Apr 11;496(7444):238–242.
  • Ortiz-Masiá D, Gisbert-Ferrándiz L, Bauset C, et al. Succinate activates EMT in Intestinal epithelial cells through SUCNR1: a novel protagonist in fistula development. Cells. 2020 Apr 29;9(5):1104.
  • Macias-Ceja DC, Ortiz-Masia D, Salvador P, et al. Succinate receptor mediates intestinal inflammation and fibrosis. Mucosal Immunol. 2019 Jan;12(1):178–187.
  • Wehling-Henricks M, Jordan MC, Gotoh T, et al. Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy. PLoS One. 2010 May 21;5(5):e10763.
  • Liu H, Drew P, Gaugler AC, et al. Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway. Am J Transplant. 2005 Jun;5(6):1256–1263.
  • Wetzel MD, Stanley K, Wang WW, et al. Selective inhibition of arginase-2 in endothelial cells but not proximal tubules reduces renal fibrosis. JCI Insight. 2020 Oct 2;5(19). DOI:10.1172/jci.insight.142187.
  • Pesce JT, Ramalingam TR, Mentink-Kane MM, et al. Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog. 2009 Apr;5(4):e1000371.
  • Boada-Romero E, Martinez J, Heckmann BL, et al. The clearance of dead cells by efferocytosis. Nat Rev Mol Cell Biol. 2020;21(7):398–414.
  • Nepal S, Tiruppathi C, Tsukasaki Y, et al. STAT6 induces expression of Gas6 in macrophages to clear apoptotic neutrophils and resolve inflammation. Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16513–16518.
  • Medina CB, Mehrotra P, Arandjelovic S, et al. Metabolites released from apoptotic cells act as tissue messengers. Nature. 2020 Apr;580(7801):130–135.
  • Patankar JV, Becker C. Cell death in the gut epithelium and implications for chronic inflammation. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):543–556.
  • Xiong W, Frasch SC, Thomas SM, et al. Induction of TGF-beta1 synthesis by macrophages in response to apoptotic cells requires activation of the scavenger receptor CD36. PLoS One. 2013;8(8):e72772.
  • Rockey DC, Bell PD, Hill JA. Fibrosis–A common pathway to organ injury and failure. N Engl J Med. 2015 Jul 2;373(1):96.
  • Scharl M, Huber N, Lang S, et al. Hallmarks of epithelial to mesenchymal transition are detectable in Crohn’s disease associated intestinal fibrosis. Clin Transl Med. 2015;4(1):1.
  • Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009 Jun;119(6):1420–1428.
  • Lovisa S, Genovese G, Danese S. Role of epithelial-to-mesenchymal transition in inflammatory bowel disease. J Crohns Colitis. 2019 Apr 26;13(5):659–668.
  • Scharl M, Frei S, Pesch T, et al. Interleukin-13 and transforming growth factor β synergise in the pathogenesis of human intestinal fistulae. Gut. 2013 Jan;62(1):63–72.
  • Li C, Vu K, Hazelgrove K, et al. Increased IGF-IEc expression and mechano-growth factor production in intestinal muscle of fibrostenotic Crohn’s disease and smooth muscle hypertrophy. Am J Physiol Gastrointest Liver Physiol. 2015 Dec 1;309(11):G888–99.
  • Drygiannakis I, Valatas V, Sfakianaki O, et al. Proinflammatory cytokines induce crosstalk between colonic epithelial cells and subepithelial myofibroblasts: implication in intestinal fibrosis. J Crohns Colitis. 2013 May;7(4):286–300.
  • Grassl GA, Valdez Y, Bergstrom KS, et al. Chronic enteric salmonella infection in mice leads to severe and persistent intestinal fibrosis. Gastroenterology. 2008;134(3):768–780.
  • Small CL, Reid-Yu SA, McPhee JB, et al. Persistent infection with Crohn’s disease-associated adherent-invasive Escherichia coli leads to chronic inflammation and intestinal fibrosis. Nat Commun. 2013;4(1):1957.
  • Sartor RB, Bond TM, Schwab JH. Systemic uptake and intestinal inflammatory effects of luminal bacterial cell wall polymers in rats with acute colonic injury. Infect Immun. 1988 Aug;56(8):2101–2108.
  • Mourelle M, Salas A, Guarner F, et al. Stimulation of transforming growth factor beta1 by enteric bacteria in the pathogenesis of rat intestinal fibrosis. Gastroenterology. 1998 Mar;114(3):519–526.
  • Jacob N, Jacobs JP, Kumagai K, et al. Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome. Mucosal Immunol. 2018 Sep;11(5):1466–1476.
  • Danne C, Ryzhakov G, Martínez-López M, et al. A large polysaccharide produced by helicobacter hepaticus induces an anti-inflammatory gene signature in macrophages. Cell Host Microbe. 2017;22(6):733–745.e5.
  • Hayashi A, Sato T, Kamada N, et al. A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice. Cell Host Microbe. 2013 Jun 12;13(6):711–722.
  • Lee C, Kim BG, Kim JH, et al. Sodium butyrate inhibits the NF-kappa B signaling pathway and histone deacetylation, and attenuates experimental colitis in an IL-10 independent manner. Int Immunopharmacol. 2017 Oct;51:47–56.
  • Caprara G, Allavena P, Erreni M. Intestinal macrophages at the crossroad between diet, inflammation, and cancer. Int J Mol Sci. 2020 Jul 8;21(14):4825.
  • Lührs H, Gerke T, Müller JG, et al. Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis. Scand J Gastroenterol. 2002 Apr;37(4):458–466.
  • Na YR, Stakenborg M, Seok SH, et al. Macrophages in intestinal inflammation and resolution: a potential therapeutic target in IBD. Nat Rev Gastroenterol Hepatol. 2019 Sep;16(9):531–543.
  • Nagatake T, Kishino S, Urano E, et al. Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques. Mucosal Immunol. 2022 Feb;15(2):289–300.
  • To S, Chavula T, Pedroza M, et al. Cadherin-11 regulates macrophage development and function. Front Immunol. 2022;13:795337.
  • Lodyga M, Cambridge E, Karvonen HM, et al. Cadherin-11-mediated adhesion of macrophages to myofibroblasts establishes a profibrotic niche of active TGF-β. Sci Signal. 2019 Jan 15;12(564). DOI:10.1126/scisignal.aao3469.
  • Xie H, Jiao Y, Zhou X, et al. Integrin αvβ6 contributes to the development of intestinal fibrosis via the FAK/AKT signaling pathway. Exp Cell Res. 2022 Feb 15;411(2):113003.
  • Wong VW, Rustad KC, Akaishi S, et al. Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling. Nat Med. 2011 Dec 11;18(1):148–152.
  • Zhao X-K, Yu L, Cheng M-L, et al. Focal adhesion kinase regulates hepatic stellate cell activation and liver fibrosis. Sci Rep. 2017;7(1):4032.
  • Mewhort HE, Lipon BD, Svystonyuk DA, et al. Monocytes increase human cardiac myofibroblast-mediated extracellular matrix remodeling through TGF-beta1. Am J Physiol Heart Circ Physiol. 2016 Mar 15;310(6):H716–24.
  • Castella LF, Buscemi L, Godbout C, et al. A new lock-step mechanism of matrix remodelling based on subcellular contractile events. J Cell Sci. 2010 May 15;123(Pt 10):1751–1760.
  • Johnson LA, Rodansky ES, Sauder KL, et al. Matrix stiffness corresponding to strictured bowel induces a fibrogenic response in human colonic fibroblasts. Inflamm Bowel Dis. 2013 Apr;19(5):891–903.
  • de Vallière C, Vidal S, Clay I, et al. The pH-sensing receptor OGR1 improves barrier function of epithelial cells and inhibits migration in an acidic environment. Am J Physiol Gastrointest Liver Physiol. 2015 Sep 15;309(6):G475–90.
  • Weder B, Schefer F, van Haaften WT, et al. New therapeutic approach for intestinal fibrosis through inhibition of ph-sensing receptor GPR4. Inflamm Bowel Dis. 2021;28(1):109–125.
  • de Vallière C, Cosin-Roger J, Baebler K, et al. pH-sensing G protein-coupled receptor OGR1 (GPR68) expression and activation increases in intestinal inflammation and fibrosis. Int J Mol Sci. 2022 Jan 26;23(3):1419.
  • Hutter S, van Haaften WT, Hünerwadel A, et al. Intestinal activation of pH-sensing receptor OGR1 [GPR68] contributes to fibrogenesis. J Crohns Colitis. 2018 Nov 15;12(11):1348–1358.
  • Tcymbarevich I, Richards SM, Russo G, et al. Lack of the pH-sensing receptor TDAG8 [GPR65] in macrophages plays a detrimental role in murine models of inflammatory bowel disease. J Crohns Colitis. 2019 Feb 1;13(2):245–258.
  • Lassen KG, McKenzie CI, Mari M, et al. Genetic coding variant in GPR65 alters lysosomal ph and links lysosomal dysfunction with colitis risk. Immunity. 2016 Jun 21;44(6):1392–1405.
  • Tcymbarevich IV, Eloranta JJ, Rossel JB, et al. The impact of the rs8005161 polymorphism on G protein-coupled receptor GPR65 (TDAG8) pH-associated activation in intestinal inflammation. BMC Gastroenterol. 2019 Jan 7;19(1):2.
  • Dvorak AM, Osage JE, Monahan RA, et al. Crohn’s disease: transmission electron microscopic studies. III. Target tissues. Proliferation of and injury to smooth muscle and the autonomic nervous system. Hum Pathol. 1980 Nov;11(6):620–634.
  • Chen W, Lu C, Hirota C, et al. Smooth muscle hyperplasia/hypertrophy is the most prominent histological change in crohn’s fibrostenosing bowel strictures: a semiquantitative analysis by using a novel histological grading scheme. J Crohns Colitis. 2017 Jan;11(1):92–104.
  • Lourenssen SR, Blennerhassett MG. M2 macrophages and phenotypic modulation of intestinal smooth muscle cells characterize inflammatory stricture formation in rats. Am J Pathol. 2020 Sep;190(9):1843–1858.
  • Kredel LI, Batra A, Stroh T, et al. Adipokines from local fat cells shape the macrophage compartment of the creeping fat in Crohn’s disease. Gut. 2013 Jun;62(6):852–862.
  • Dickson I. Creeping fat in Crohn’s disease explained. Nat Rev Gastroenterol Hepatol. 2020 Dec;17(12):713.
  • CWY H, Martin A, Sepich-Poore GD, et al. Translocation of viable gut microbiota to mesenteric adipose drives formation of creeping fat in humans. Cell. 2020 Oct 29;183(3):666–683.e17.
  • Shook BA, Wasko RR, Rivera-Gonzalez GC, et al. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science. 2018;362(6417):eaar2971.
  • Schnitzler F, Friedrich M, Angelberger M, et al. Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn’s disease and active smoking status resulting in ileal stenosis requiring surgery. PLoS One. 2020;15(7):e0236421.
  • Adler J, Rangwalla SC, Dwamena BA, et al. The prognostic power of the NOD2 genotype for complicated Crohn’s disease: a meta-analysis. Am J Gastroenterol. 2011 Apr;106(4):699–712.
  • Lesage S, Zouali H, Cézard J-P, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002;70(4):845–857.
  • Sabate JM, Ameziane N, Lamoril J, et al. The V249I polymorphism of the CX3CR1 gene is associated with fibrostenotic disease behavior in patients with Crohn’s disease. Eur J Gastroenterol Hepatol. 2008 Aug;20(8):748–755.
  • Picornell Y, Mei L, Taylor K, et al. TNFSF15 is an ethnic-specific IBD gene. Inflamm Bowel Dis. 2007 Nov;13(11):1333–1338.
  • Michelsen KS, Thomas LS, Taylor KD, et al. IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein. PLoS One. 2009;4(3):e4719.
  • Shih DQ, Zheng L, Zhang X, et al. Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal Immunol. 2014 Nov;7(6):1492–1503.
  • Bouhnik Y, Carbonnel F, Laharie D, et al. Efficacy of Adalimumab in patients with Crohn’s disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study. Gut. 2018 Jan;67(1):53–60.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.