IL-17-driven intestinal fibrosis is inhibited by Itch-mediated ubiquitination of HIC-5

Paul, Jaishree; Singh, Amir Kumar; Kathania, Mahesh; Elviche, T L; Zeng, Minghui; Basrur, Venkatesha; Theiss, Arianne L.; Venuprasad, K.

doi:10.1038/mi.2017.53

Cited by 18 publications

(15 citation statements)

References 45 publications

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“…It was later revealed that high levels of IL‐17 contributed to the spontaneous GI inflammation that occurred in Itch‐deficient mice. This GI inflammation resembled inflammatory bowel disease and was accompanied by colonic fibrosis 18,19 . Consistent with this, mice lacking the Itch activator Ndfip1 also develop severe IL‐17‐mediated GI inflammation, supporting that active Itch is required to prevent intestinal disease in mice 20 .…”

Section: Itch‐deficient Mice Show Altered T Cell Responses and Inflamsupporting

confidence: 56%

“…Supporting this, Itch‐deficient Th17 cells give rise to more pathogenic Th17 cells that drive colitis 18,36 . Exacerbation of colitis in Itch‐deficient mice can also be due to excessive IL‐17 responsiveness, as it has been reported that Itch‐deficient myofibroblasts showed increased sensitivity to IL‐17 signaling, resulting in increased fibrosis 19 . Thus, both the lung and GI aspects of Itch deficiency are the consequence of an interplay between the dysregulated innate and adaptive immune cells…”

Section: Itch Regulation Of T Cell Fatementioning

confidence: 93%

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Itch regulation of innate and adaptive immune responses in mice and humans

Field

Moser

Oliver

2020

Journal of Leukocyte Biology

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The E3 ubiquitin ligase Itch has long been appreciated to be a critical suppressor of inflammation, first identified as a regulator of Th2 differentiation and lung inflammation. Recent studies have revealed novel roles for this protein in mouse and human disease, and it is now clear that Itch also limits the function of other lymphocytes, innate immune cells, and nonhematopoietic cells to regulate immunity. In addition to Th2 cells, Itch also regulates Th17 and regulatory T cells. Itch regulates humoral immunity through direct roles in T follicular helper cells and T follicular regulatory cells, and B cells. Furthermore, Itch limits innate immune responses, such as macrophage cytokine production. Through these cell‐intrinsic functions, Itch regulates the interplay between innate and adaptive immune cells, resulting in profound autoinflammation in Itch‐deficient mice. Whereas Itch deficiency was previously thought to be an extremely rare occurrence humans, whole exome sequencing of patients with unexplained autoimmune disease has revealed at least two additional cases of Itch deficiency in the last year alone, each caused by distinct mutations within the Itch gene. The recent identification of these patients suggests that Itch mutations may be more common than previously thought, and demonstrates the need to understand how this protein regulates inflammation and autoimmune disease.

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Section: Itch‐deficient Mice Show Altered T Cell Responses and Inflamsupporting

confidence: 56%

Section: Itch Regulation Of T Cell Fatementioning

confidence: 93%

Itch regulation of innate and adaptive immune responses in mice and humans

Field

Moser

Oliver

2020

Journal of Leukocyte Biology

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“…28 The level of IL-17 is elevated in the intestine of IBD patients, where the cytokine facilitates intestinal fibrosis. 24,29 Likewise, IL-23 induced-expression of IL-22 is observed in psoriasis, 30 rheumatoid arthritis, 31 and IBD. 32,33 CX3Cr1 + mononuclear phagocytes promote the production of IL-22 from ILC3 cells via IL-23.…”

Section: Introductionmentioning

confidence: 99%

Induction of autophagy in Cx3cr1+ mononuclear cells limits IL-23/IL-22 axis-mediated intestinal fibrosis

et al. 2019

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Intestinal fibrosis is an excessive proliferation of myofibroblasts and deposition of collagen, a condition frequently seen in Crohn’s disease (CD). The mechanism underlying myofibroblast hyper-proliferation in CD needs to be better understood. In this report, we found that mTOR inhibitor rapamycin or mTOR deletion in CX3Cr1+ mononuclear phagocytes inhibits expression of interleukin (IL) −23, accompanied by reduced intestinal production of IL-22 and ameliorated fibrosis in the TNBS-induced fibrosis mouse model. This inhibition of IL-23 expression is associated with elevated autophagy activity. Ablating the autophagy gene Atg7 increases the expression of IL-23, leading to increased expression of IL-22 and increased fibrosis. Both induction of IL-22 and intestinal fibrosis occurred in RAG−/− mice and depletion of innate lymphoid cells (ILCs) attenuates the fibrotic reaction, suggesting that the pro-fibrotic process is independent of T and B cells. Moreover, IL-22 facilitates the transformation of fibroblasts into myofibroblasts. Finally, the fibrotic reaction was attenuated upon neutralization of either IL-23 or IL-22. Altogether, this study elucidated a signaling cascade underlying intestinal fibrosis in which altered mTOR/autophagy in CX3Cr1+ mononuclear phagocytes up-regulates the IL-23/IL-22 axis, leading to an excessive fibrotic response. Thus, our findings suggest that this cascade could be a therapeutic target for alleviation of CD fibrosis.

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“…During tissue injury with a chemical, mechanical and infection condition, an inflammatory response triggers the tissue repair process. However, a dysregulated and pathological inflammatory response leads to developing scarring or a fibrotic reaction, which could impair the tissue repair function 9,18,19 . Here, we show the procedure for the TNBS-induced fibrosis animal model, which significantly shares pathophysiology with human Crohn's disease.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin

Mathur

Alam

Zhao

et al. 2019

JoVE

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Significant studies have been carried out to understand effective management of intestinal fibrosis. However, the lack of better knowledge of fibrosis has hindered the development of a preventative drug. Primarily, finding a suitable animal model is challenging in understanding the mechanism of Crohn's-associated intestinal fibrosis pathology. Here, we adopted an effective method where TNBS chemical exposure to mice rectums produces substantially deep ulceration and chronic inflammation, and the mice then chronically develop intestinal fibrosis. Also, we describe a technique where a rapamycin injection shows inhibitory effects on TNBS-mediated fibrosis in the mouse model. To assess the underlying mechanism of fibrosis, we methodically discuss a procedure for purifying Cx3Cr1+ cells from the lamina propria of TNBS-treated and control mice. This detailed protocol will be helpful to researchers who are investigating the mechanism of fibrosis and pave the path to find a better therapeutic invention for Crohn's-associated intestinal fibrosis.

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IL-17-driven intestinal fibrosis is inhibited by Itch-mediated ubiquitination of HIC-5

Cited by 18 publications

References 45 publications

Itch regulation of innate and adaptive immune responses in mice and humans

Itch regulation of innate and adaptive immune responses in mice and humans

Induction of autophagy in Cx3cr1+ mononuclear cells limits IL-23/IL-22 axis-mediated intestinal fibrosis

Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin

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