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

Mao, Ren; Rieder, Florian

doi:10.1053/j.gastro.2019.02.007

Cited by 7 publications

(11 citation statements)

References 19 publications

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“…IL-36α secreted from inflammatory macrophages appears to bind to IL-36R of intestinal myofibroblasts located adjacent to macrophages and subsequently induces collagen VI production and proliferation in myofibroblasts. [58][59][60] Knockout of the IL-36R gene or neutralizing of the IL-36R reduced intestinal fibrosis in mouse models. 58 TNF like cytokine 1A (TL1A) secreted from immune cells binds to death domain receptor 3 (DR3) expressed in intestinal myofibroblasts, and consequently increases collagen production and proliferation in myofibroblasts, leading to intestinal fibrosis in CD strictures.…”

Section: Cellular and Soluble Mediators Of Fibrosismentioning

confidence: 99%

Fibrostenotic strictures in Crohn’s disease

2020

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reported in 85%-100% of cases 7,10 and fibrostenotic stricture is the most common indication for surgery in CD. 3,9 Surgical resection is related with major morbidity, higher costs, higher risk of unemployment, and poorer quality of life. 3,11,12 Although the introduction of biologics including anti-TNF, anti-integrin, and anti-interleukin (IL) has modified the disease course of CD in the short term, the long-term outcome of those drugs on the development of fibrostenosis and the need for surgery remains to be elucidated. 5 Fibrostenotic strictures were previously considered an inevitable and irreversible consequence of long-term inflammation in CD patients whose conditions are unresponsive to anti-inflammatory therapies. This paradigm has been changing rapidly due to recent advances in our understanding regarding the process of intestinal fibrosis and the introduction of promising candidates for targeted anti-fibrotic therapy. 1 This review aimed to provide a comprehensive overview of fibrostenotic strictures in CD, including mechanisms and factors that predict its progression, as well as diagnosis and treatment strategies. It also introduces promising anti-fibrotic agents for intestinal fibrosis and discuss the obstacles to be overcome in developing clinically available anti-fibrotic agents for CD stricture.

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Section: Cellular and Soluble Mediators Of Fibrosismentioning

confidence: 99%

Fibrostenotic strictures in Crohn’s disease

2020

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“…The two murine chronic experimental models for chronic colitis and fibrosis, TNBS and DSS, blockade of IL-36R signalling results in ameliorated intestinal inflammation and fibrosis. 17,57 Currently, clinical trials targeting IL-36R signalling with neutralizing antibodies are ongoing for the treatment of IBD. [58][59][60] Acute and bacterial-induces intestinal inflammation…”

Section: Il-36 and Chronic Intestinal Inflammationmentioning

confidence: 99%

“…Second, intestinal fibrosis is the most common complication of IBD, and currently, there are no specific anti-fibrotic therapies; since IL-36 stimulates fibrosis/tissue remodelling mediators such as TGF-b and matrix metalloproteinases (MMPs) in human and mice myofibroblasts, inhibition of IL-36R signalling could also avert intestinal fibrosis in IBD patients. 17,57,63 Current tools used to block IL-36R signalling…”

Section: Potential For Treating Ibd By Blocking Il-36rmentioning

confidence: 99%

IL‐36 cytokines and gut immunity

et al. 2021

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Interleukin 36 (IL-36) constitutes a group of cytokines that belong to the IL-1 superfamily. Emerging evidence has suggested a role of IL-36 in the pathogenesis of many inflammatory disorders. Intriguingly, in the gastrointestinal tract, IL-36 has a rather complex function. IL-36 receptor ligands are overexpressed in both animal colitis models and human IBD patients and may play both pathogenic and protective roles, depending on the context. IL-36 cytokines comprise three receptor agonists: IL-36a, IL-36b and IL-36c, and two receptor antagonists: IL-36Ra and IL-38. All IL-36 receptor agonists bind to the IL-36R complex and exert pleiotropic effects during inflammatory settings. Here, we first briefly review the processing and secretion of IL-36 cytokines. We then focus on the current understanding of the immunology effects of IL-36 in gut immunity. In addition, we also discuss the ongoing trials that aim to blockage IL-36R signalling for treating chronic intestinal inflammation and present some unexplored questions regarding IL-36 research.

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“…The NKG2D receptor is a type II transmembrane protein expressed by both innate and adaptive immune cells, including natural killer (NK) cells, CD8 + T cells, invariant NKT cells, gd T cells, and some CD4 + T cells under certain pathological conditions (Stojanovic et al, 2018). In particular, when activated, both macrophages and DCs upregulate NKG2D, thereby enabling them with additional mechanisms for regulating lymphocyte responses (Mao and Rieder, 2019). On this basis, blocking NKG2D would be another new mechanism of action for moderate to severe CD patients, as highlighted by the evidence about a significant increase in clinical remission in CD patients treated with an anti-NKG2D antibody (Vadstrup and Bendtsen, 2017).…”

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confidence: 99%

“…The IL-36 cytokine family, produced predominantly by epithelial cells, acts on several cells including the immune cells, epithelial cells, and fibroblasts and is increased in IBD patients, thus representing another interesting target to manage bowel inflammation (Bassoy et al, 2018). In this regard, anti-IL36R antibodies are entering phase II trials in patients with moderate to severe ulcerative colitis (UC) (Mao and Rieder, 2019).…”

mentioning

confidence: 99%