Role of Nox4 in Mitigating Inflammation and Fibrosis in Dextran Sulfate Sodium-Induced Colitis
- 주제(키워드) Fibrostenotic CD , T-Cell Lineage Commitment , RNA-Sequencing , Oxidative Stress
- 주제(기타) Gastroenterology & Hepatology
- 설명문(일반) [Lee, Yura; Kim, Sung-Hee; Jeong, Haengdueng; Kim, Kwang H.; Jeon, Donghun; Cho, Yejin; Nam, Ki Taek] Yonsei Univ, Severance Biomed Sci Inst, Brain Korea 21 PLUS Project Med Sci, Coll Med, Seoul, South Korea; [Lee, Daekee] Ewha Womans Univ, Dept Life Sci, Seoul, South Korea; [Nam, Ki Taek] Yonsei Univ, Severance Biomed Sci Inst, Coll Med, 50-1 Yonsei Ro, Seoul, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Published, gold
- 발행기관 ELSEVIER INC
- 발행년도 2023
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000211479
- 본문언어 영어
- Published As https://doi.org/10.1016/j.jcmgh.2023.05.002
- PubMed 37207801
초록/요약
BACKGROUND & AIMS: Fibrosis development in ulcerative colitis is associated directly with the severity of mucosal inflammation, which increases the risk of colorectal cancer. The transforming growth factor -5 (TGF-5) signaling pathway is an important source of tissue fibrogenesis, which is stim-ulated directly by reactive oxygen species produced from nicotinamide adenine dinucleotide phosphate oxidases (NOX). Among members of the NOX family, NOX4 expression is up -regulated in patients with fibrostenotic Crohn's disease (CD) and in dextran sulfate sodium (DSS)-induced murine colitis. The aim of this study was to determine whether NOX4 plays a role in fibrogenesis during inflammation in the colon using a mouse model.METHODS: Acute and recovery models of colonic inflamma-tion were performed by DSS administration to newly gener-ated Nox4-/-mice. Pathologic analysis of colon tissues was performed, including detection of immune cells, proliferation, and fibrotic and inflammatory markers. RNA sequencing was performed to detect differentially expressed genes between Nox4-/-and wild-type mice in both the untreated and DSS-treated conditions, followed by functional enrichment anal-ysis to explore the molecular mechanisms contributing to pathologic differences during DSS-induced colitis and after recovery.RESULTS: Nox4-/-mice showed increased endogenous TGF-5 signaling in the colon, increased reactive oxygen species levels, intensive inflammation, and an increased fibrotic region after DSS treatment compared with wild-type mice. Bulk RNA sequencing confirmed involvement of canonical TGF-5 signaling in fibrogenesis of the DSS-induced colitis model. Up -regulation of TGF-5 signaling affects collagen activation and T-cell lineage commitment, increasing the susceptibility for inflammation.CONCLUSIONS: Nox4 protects against injury and plays a crucial role in fibrogenesis in DSS-induced colitis through canonical TGF-5 signaling regulation, highlighting a new treatment target. (Cell Mol Gastroenterol Hepatol 2023
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