Cooling Down the Hot Potato: Anti-Interleukin 36 Therapy Prevents and Treats Experimental Intestinal Fibrosis

See “Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation,” by Scheibe K, Kersten C, Schmied A, et al, on page 1082. See “Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation,” by Scheibe K, Kersten C, Schmied A, et al, on page 1082. The majority of patients with Crohn’s disease (CD) experience fibrosis associated complications over their lifetime culminating in need for resection.1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350 e6Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar Increasing evidence suggests that fibrosis is also common and clinically relevant in the colon of patients with ulcerative colitis, with clinical implications such as urgency or diarrhea.2Gordon I.O. Agrawal N. Willis E. et al.Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation.Aliment Pharmacol Ther. 2018; 47: 922-939Crossref PubMed Scopus (70) Google Scholar Intestinal fibrosis represents perhaps the most significant remaining challenge in the field of inflammatory bowel diseases (IBD) because specific antifibrotic therapies are currently not available.1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350 e6Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar Intestinal mesenchymal cells (including fibroblasts, myofibroblasts, and smooth muscle cells) are considered the main effector cells in intestinal fibrosis through their ability to secrete extracellular matrix.1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350 e6Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar They can be activated by soluble factors, such as cytokines, chemokines, and growth factors from neighboring cells, including immune and nonimmune cells (epithelial cells, endothelial cells, fat cells). If excessive, this process ultimately leads to accumulation of extracellular matrix molecules such as collagens or fibronectins and increased tissue stiffness.3Mao R. Kurada S. Gordon I.O. et al.The mesenteric fat and intestinal muscle interface: creeping fat influencing stricture formation in Crohn's disease.Inflamm Bowel Dis. 2018 Oct 19; ([E-pub ahead of print])Crossref Scopus (73) Google Scholar Recently, IL-36 cytokines (IL-36α, IL-36β, and IL-36γ) were identified as potent activators of fibroblasts in the pancreas and kidney, making IL-36 and its downstream signaling pathways a potential target for the treatment of inflammation and fibrosis.4Chi H.H. Hua K.F. Lin Y.C. et al.IL-36 Signaling facilitates activation of the NLRP3 inflammasome and IL-23/IL-17 axis in renal inflammation and fibrosis.J Am Soc Nephrol. 2017; 28: 2022-2037Crossref PubMed Scopus (88) Google Scholar, 5Nishida A. Inatomi O. Fujimoto T. et al.Interleukin-36alpha induces inflammatory mediators from human pancreatic myofibroblasts via a MyD88 dependent pathway.Pancreas. 2017; 46: 539-548Crossref PubMed Scopus (19) Google Scholar As a member of the IL-1 family, IL-36 transduces signals via binding to a heterodimeric receptor complex composed of IL36R and its co-receptor IL-1R accessory protein (IL-1RAcP).6Towne J.E. Garka K.E. Renshaw B.R. et al.Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs.J Biol Chem. 2004; 279: 13677-13688Crossref PubMed Scopus (333) Google Scholar Previous studies in IBD indicate that IL-36R signaling is activated in the IBD mucosa.7Nishida A. Hidaka K. Kanda T. et al.Increased expression of interleukin-36, a member of the interleukin-1 cytokine family, in inflammatory bowel disease.Inflamm Bowel Dis. 2016; 22: 303-314Crossref PubMed Scopus (90) Google Scholar Inhibition of IL-36R signaling exhibited reduced disease severity in acute dextran sodium sulfate (DSS) and Citrobacter rodentium colitis in one study,8Russell S.E. Horan R.M. Stefanska A.M. et al.IL-36alpha expression is elevated in ulcerative colitis and promotes colonic inflammation.Mucosal Immunol. 2016; 9: 1193-1204Crossref PubMed Scopus (93) Google Scholar but caused worsening of acute DSS colitis and an impairment of wound healing in other studies.7Nishida A. Hidaka K. Kanda T. et al.Increased expression of interleukin-36, a member of the interleukin-1 cytokine family, in inflammatory bowel disease.Inflamm Bowel Dis. 2016; 22: 303-314Crossref PubMed Scopus (90) Google Scholar, 9Scheibe K. Backert I. Wirtz S. et al.IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo.Gut. 2017; 66: 823-838Crossref PubMed Scopus (110) Google Scholar, 10Medina-Contreras O. Harusato A. Nishio H. et al.Cutting edge: IL-36 receptor promotes resolution of intestinal damage.J Immunol. 2016; 196: 34-38Crossref PubMed Scopus (101) Google Scholar This raised concerns about the therapeutic use of this pathway in human IBD, which made anti-IL36 therapy a potentially “hot potato.” In this issue of Gastroenterology, Scheibe et al11Scheibe K. Kersten C. Schmied A. et al.Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation.Gastroenterology. 2019; 156: 1082-1097Abstract Full Text Full Text PDF Scopus (99) Google Scholar performed a timely investigation of a putative role of IL-36R signaling in chronic intestinal inflammation and fibrosis (Figure 1).11Scheibe K. Kersten C. Schmied A. et al.Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation.Gastroenterology. 2019; 156: 1082-1097Abstract Full Text Full Text PDF Scopus (99) Google Scholar IL-36α–positive, but not IL-36γ–positive cells, were found to be increased in stenotic CD regions compared with controls, and were located adjacent to α-smooth muscle actin–positive myofibroblasts and smooth muscle cells. Cells expressing IL-36α were positive for CD14, CD64, and CD163, indicating that they are inflammatory and tissue-resident macrophages. RNA sequencing in both human and murine samples revealed IL-36R signaling as a regulator of fibrosis and tissue remodeling genes. Chronic systemic administration of IL-36R ligands increased the number of α-smooth muscle actin–positive cells. In 2 commonly accepted chronic experimental colitis and fibrosis models, trinitrobenzene sulfonic acid and DSS, both defective IL-36R signaling (mice deficient in IL36R) and preventive blockade of IL-36R signaling (via antibody injection) decreased intestinal inflammation and fibrosis. Importantly, antibody-mediated inhibition of IL-36R reversed the established experimental intestinal fibrosis and also ameliorated inflammation.11Scheibe K. Kersten C. Schmied A. et al.Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation.Gastroenterology. 2019; 156: 1082-1097Abstract Full Text Full Text PDF Scopus (99) Google Scholar IL-36R is expressed on cell types other than fibroblasts, including immune cells, which could indirectly contribute to fibrosis.11Scheibe K. Kersten C. Schmied A. et al.Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation.Gastroenterology. 2019; 156: 1082-1097Abstract Full Text Full Text PDF Scopus (99) Google Scholar The authors of the current study elegantly used bone marrow chimeras to show that IL-36R signaling in the hematopoietic compartment is not critical in experimental fibrogenesis. What raises great interest in this study is the opposing effect of IL-36R signaling on the regulation of acute compared with chronic colonic inflammation. This has also been observed with tumor necrosis factor blockade previously,12Kojouharoff G. Hans W. Obermeier F. et al.Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice.Clin Exp Immunol. 1997; 107: 353-358Crossref PubMed Scopus (286) Google Scholar, 13Noti M. Corazza N. Mueller C. et al.TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis.J Exp Med. 2010; 207: 1057-1066Crossref PubMed Scopus (126) Google Scholar and may be ascribed to changing mechanisms of inflammation in early compared with late disease. Chronic DSS models depend more on the activation of innate and adaptive immune cells, although acute DSS is thought to occur independently of changes in T-cell activation.14Rieder F. Kessler S. Sans M. et al.Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G786-G801Crossref PubMed Scopus (100) Google Scholar, 15Wirtz S. Neufert C. Weigmann B. et al.Chemically induced mouse models of intestinal inflammation.Nat Protoc. 2007; 2: 541-546Crossref PubMed Scopus (1151) Google Scholar Cytokine profiles change from a T-helper (Th)1-type in early disease, to a predominantly Th2-type inflammatory response associated with fibrosis in late disease.16Kugathasan S. Saubermann L.J. Smith L. et al.Mucosal T-cell immunoregulation varies in early and late inflammatory bowel disease.Gut. 2007; 56: 1696-1705Crossref PubMed Scopus (162) Google Scholar, 17Fichtner-Feigl S. Fuss I.J. Young C.A. et al.Induction of IL-13 triggers TGF-beta1-dependent tissue fibrosis in chronic 2,4,6-trinitrobenzene sulfonic acid colitis.J Immunol. 2007; 178: 5859-5870Crossref PubMed Scopus (172) Google Scholar The opposing effects of IL-36R signaling may underline a crucial role of fibroblasts in regulating the switch from acute resolving to chronic persistent inflammation,18Buckley C.D. Pilling D. Lord J.M. et al.Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation.Trends Immunol. 2001; 22: 199-204Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar with inflammation in chronic colitis being driven by activated fibroblasts producing cytokines and chemokines. What remains curious is the increased secretion specifically of collagen VI in fibroblasts upon exposure to IL-36. The major collagens reported to be elevated in intestinal strictures are collagens type I and III.1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350 e6Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar This finding may suggest a distinct regulation of collagen expression by IL-36.11Scheibe K. Kersten C. Schmied A. et al.Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation.Gastroenterology. 2019; 156: 1082-1097Abstract Full Text Full Text PDF Scopus (99) Google Scholar What remains to be determined, however, are the specific signaling and synthesis pathways responsible for the secretion of collagen VI. Conclusive evidence for the role of IL-36R in fibroblasts may be obtained by using fibroblast specific deletion of IL-36R in experimental fibrosis. Because CD will likely be the first application of an antifibrotic in clinical practice, it could be informative to test IL-36 blockade in models of ileitis, such as the SampYit mouse.14Rieder F. Kessler S. Sans M. et al.Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease.Am J Physiol Gastrointest Liver Physiol. 2012; 303: G786-G801Crossref PubMed Scopus (100) Google Scholar The number of IL-36 positive cells correlated with the degree of inflammation in this study from Scheibe et al. Suppression of inflammation to date has not had a significant impact on the prevention or treatment of intestinal fibrosis and IL-36 blockade may thus not explain the inflammation-independent progression of tissue damage.1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350 e6Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar For future antifibrotic therapy approaches, it needs to be kept in mind that it is not excessive extracellular matrix deposition, but a thickening of the muscularis propria may be the main cause of luminal narrowing in fibrostenosing CD.3Mao R. Kurada S. Gordon I.O. et al.The mesenteric fat and intestinal muscle interface: creeping fat influencing stricture formation in Crohn's disease.Inflamm Bowel Dis. 2018 Oct 19; ([E-pub ahead of print])Crossref Scopus (73) Google Scholar In summary, Scheibe et al11Scheibe K. Kersten C. Schmied A. et al.Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation.Gastroenterology. 2019; 156: 1082-1097Abstract Full Text Full Text PDF Scopus (99) Google Scholar are to be congratulated on their work given its thorough nature and its translational relevance. Neutralizing antibodies targeting IL-36R are entering phase II trials in moderate to severe ulcerative colitis (EudraCT 2017-004230-28 and NCT03482635). The fact that IL-36 blockade had therapeutic effects in chronic inflammation is encouraging and is de-risking this approach, because IBD patients at diagnosis almost invariably already exhibit chronic changes owing to a latent preclinical IBD phase. Looking beyond purely treating inflammation, the progress in the field of treating intestinal strictures has been hampered by the lack of validated trial endpoints. A larger international effort (the CrOhN’S disease anti-fibrotic STRICTure Therapies [CONSTRICT] group) is currently underway to build a pathway to test antifibrotics by developing and validating a patient-reported outcome tool and radiology indices.19Rieder F. Bettenworth D. Ma C. et al.An expert consensus to standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Crohn's disease.Aliment Pharmacol Ther. 2018; 48: 347-357Crossref PubMed Scopus (111) Google Scholar This work is intended to open the door for the development of novel therapies for one of the largest unmet needs in the area of IBD, and anti–IL-36 therapy may be a promising candidate. Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice With Chronic Intestinal InflammationGastroenterologyVol. 156Issue 4PreviewIntestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) that frequently results in functional damage, bowel obstruction, and surgery. Interleukin (IL) 36 is a group of cytokines in the IL1 family with inflammatory effects. We studied the expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in the development of intestinal fibrosis in human tissues and mice. Full-Text PDF