USP2 promotes experimental colitis and bacterial infections by inhibiting the proliferation of myeloid cells and remodeling the extracellular matrix network

Ran An; Peng Wang; Hao Guo; Tianzi Liuyu; Bo Zhong; Zhi-Dong Zhang

doi:10.1016/j.cellin.2022.100047

USP2 promotes experimental colitis and bacterial infections by inhibiting the proliferation of myeloid cells and remodeling the extracellular matrix network

Cell Insight. 2022 Jul 8;1(4):100047. doi: 10.1016/j.cellin.2022.100047. eCollection 2022 Aug.

Authors

Ran An^{1

2

3}, Peng Wang^{1

2}, Hao Guo^{1

2}, Tianzi Liuyu², Bo Zhong^{1

2

3}, Zhi-Dong Zhang^{1

2

3}

Affiliations

¹ Department of Gastrointestinal Surgery, College of Life Sciences, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
² Department of Immunology, Medical Research Institute and Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430072, China.
³ Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, 430071, China.

Abstract

Inflammatory bowel disease (IBD) is closely associated with dysregulation of genetic factors and microbial environment. Here, we report a susceptible role of ubiquitin-specific protease 2 (USP2) in experimental colitis and bacterial infections. USP2 is upregulated in the inflamed mucosa of IBD patients and in the colon of mice treated with dextran sulfate sodium salt (DSS). Knockout or pharmacologic inhibition of USP2 promotes the proliferation of myeloid cells to activate IL-22 and IFNγ production of T cells. In addition, knockout of USP2 in myeloid cells inhibits the production of pro-inflammatory cytokines to relieve the dysregulation of extracellular matrix (ECM) network and promote the gut epithelial integrity after DSS treatment. Consistently, Lyz2-Cre;Usp2^fl/fl mice exhibit hyper-resistance to DSS-induced colitis and Citrobacter rodentium infections compared to Usp2^fl/fl mice. These findings highlight an indispensable role of USP2 in myeloid cells to modulate T cell activation and epithelial ECM network and repair, indicating USP2 as a potential target for therapeutic intervention of IBD and bacterial infections in the gastrointestinal system.

Keywords: Bacterial infection; Cell proliferation; Colitis; Myeloid cells; USP2.