Nogo-B inhibition restricts ulcerative colitis via inhibiting p68/miR-155 signaling pathway

Juan Zheng; Shengnan Wang; Tingting Zhang; Huaxin Li; Mengmeng Zhu; Xiaoning Wei; Yu Ge; Xiaoxiao Yang; Shuang Zhang; Hongmei Xu; Yajun Duan; Lipei Liu; Yuanli Chen

doi:10.1016/j.intimp.2023.110378

Nogo-B inhibition restricts ulcerative colitis via inhibiting p68/miR-155 signaling pathway

Int Immunopharmacol. 2023 Jul:120:110378. doi: 10.1016/j.intimp.2023.110378. Epub 2023 May 25.

Authors

Affiliations

¹ Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
² Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
³ College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
⁴ Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address: chenyuanli@hfut.edu.cn.

PMID: 37244119
DOI: 10.1016/j.intimp.2023.110378

Abstract

Background & aims: Ulcerative colitis (UC) is a main type of inflammatory bowel diseases which spreads globally during the westernization of lifestyle over the past few decades. However, the cause of UC is still not fully understood. We aimed to disclose the role of Nogo-B in the development of UC.

Methods: Nogo-deficiency (Nogo^-/-) and wild-type male mice were treated with dextran sodium sulfate (DSS) to conduct a UC model, followed by determination of colon and serum inflammatory cytokines level. RAW264.7, THP1 and NCM460 cells were used to determine macrophage inflammation as well as proliferation and migration of NCM460 cells under Nogo-B or miR-155 intervention.

Results: Nogo deficiency significantly reduced DSS-induced weight loss, colon length and weight reduction, and inflammatory cells accumulation in the intestinal villus, while increased the expression of tight junctions (TJs) proteins (Zonula occludens-1, Occludin) and adherent junctions (AJs) proteins (E-cadherin, α-catenin), implying that Nogo deficiency attenuated DSS-induced UC. Mechanistically, Nogo-B deficiency reduced TNFα, IL-1β and IL-6 levels in the colon, serum, RAW264.7 cells and THP1-derived macrophages. Furthermore, we identified that Nogo-B inhibition can reduce the maturation of miR-155, which is essential for Nogo-B-affected inflammatory cytokines expression. Interestingly, we determined that Nogo-B and p68 can interact with each other to promote the expression and activation of Nogo-B and p68, thus facilitating miR-155 maturation to induce macrophage inflammation. Blocking p68 inhibited Nogo-B, miR-155, TNFα, IL-1β and IL-6 expression. Moreover, the culture medium collected from Nogo-B overexpressed macrophages can inhibit enterocytes NCM460 cells proliferation and migration.

Conclusion: We disclose that Nogo deficiency reduced DSS-induced UC via inhibiting p68-miR-155-activated inflammation. Our results indicate that Nogo-B inhibition serves as a new potential therapeutic candidate for the prevention and treatment of UC.

Keywords: Inflammation; Nogo-B; P68; Ulcerative colitis; miR-155.

MeSH terms

Animals
Colitis, Ulcerative* / chemically induced
Colitis, Ulcerative* / drug therapy
Colitis, Ulcerative* / metabolism
Colon / metabolism
Cytokines / metabolism
Dextran Sulfate
Disease Models, Animal
Inflammation / drug therapy
Interleukin-6 / metabolism
Male
Mice
Mice, Inbred C57BL
MicroRNAs* / genetics
MicroRNAs* / metabolism
Signal Transduction
Tumor Necrosis Factor-alpha / metabolism

Substances

Tumor Necrosis Factor-alpha
Interleukin-6
Cytokines
MicroRNAs
Dextran Sulfate
Mirn155 microRNA, mouse