MCPIP1 restrains mucosal inflammation by orchestrating the intestinal monocyte to macrophage maturation via an ATF3-AP1S2 axis

促炎细胞因子 川地163 单核细胞 巨噬细胞 免疫学 趋化因子 CCR2型 CD11c公司 整合素αM 炎症 肠粘膜 医学 生物 免疫系统 内科学 趋化因子受体 体外 表型 基因 生物化学
作者
Huiying Lu,Cui Zhang,Wei Wu,Huimin Chen,Ritian Lin,Ruicong Sun,Xiang Gao,Gengfeng Li,Qiong He,Han Gao,Xiaohan Wu,Jian Lin,Ruixin Zhu,Jianli Niu,Pappachan E. Kolattukudy,Zhanju Liu
出处
期刊:Gut [BMJ]
卷期号:72 (5): 882-895 被引量:19
标识
DOI:10.1136/gutjnl-2022-327183
摘要

Objective Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) is highly expressed in inflamed mucosa of inflammatory bowel disease (IBD) and negatively regulates immune response, while the underlying mechanisms regulating mucosal macrophage functions remain unknown. Here, we investigated the roles of MCPIP1 in modulating the differentiation and functions of intestinal macrophages in the pathogenesis of IBD. Design ScRNA-seq was used to cluster the monocyte/macrophage lineage from macrophage-specific Mcpip1 -deficient ( Mcpip1 ∆Mye ) mice and Mcpip1 fl/fl littermates. The differentially expressed genes were confirmed by RNA-seq, luciferase assay, CUT&Tag assay and Western blotting. Effects of MCPIP1 and the activating transcription factor 3 (ATF3)-AP1S2 axis were assessed in patients with IBD. Results Mcpip1 ∆Mye mice developed more severe dextran sulfate sodium (DSS)-induced colitis characterised by an increase in macrophage migratory capacity and M1 macrophage polarisation but a decrease in the monocyte-to-macrophage maturation in gut mucosa compared with their littermates. ScRNA-seq unravelled a proinflammatory population (Ccr2 + Il-1β + Tlr2 + Cx3cr1 − Cd163 − Mrc1 − Ly6c + ) of the monocyte/macrophage lineage from lamina propria CD11b + cells and an arrest of Mcpip1 ∆Mye monocyte-to-macrophage maturation in an Atf3-Ap1s2 axis-dependent manner. Silencing of Ap1s2 or Atf3 markedly suppressed Mcpip1 ∆Mye macrophage migration, M1-like polarisation, and production of proinflammatory cytokines and chemokines. Notably, in vivo blockage of Ap1s2 ameliorated DSS-induced colitis in Mcpip1 ΔMye mice through enhancing intestinal macrophage maturation. Furthermore, MCPIP1, ATF3 and AP1S2 were highly expressed in inflamed mucosa of active patients with IBD and blockage of ATF3 or AP1S2 significantly suppressed IBD CD14 + -derived M1-like macrophage polarisation and proinflammatory cytokine production. Conclusions Macrophage-specific Mcpip1 deficiency polarises macrophages towards M1-like phenotype, arrests macrophage maturation and exacerbates intestinal inflammation in an Atf3-Ap1s2-dependent manner, thus providing novel mechanistic insight into intestinal macrophage functions during IBD.
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