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Original research
MCPIP1 restrains mucosal inflammation by orchestrating the intestinal monocyte to macrophage maturation via an ATF3-AP1S2 axis
  1. Huiying Lu1,
  2. Cui Zhang1,
  3. Wei Wu1,
  4. Huimin Chen1,
  5. Ritian Lin1,
  6. Ruicong Sun1,
  7. Xiang Gao1,
  8. Gengfeng Li1,
  9. Qiong He1,
  10. Han Gao1,
  11. Xiaohan Wu1,
  12. Jian Lin1,
  13. Ruixin Zhu2,
  14. Jianli Niu3,4,
  15. Pappachan E Kolattukudy4,
  16. Zhanju Liu1
  1. 1Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
  2. 2Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai, China
  3. 3Office of Human Research, Memorial Healthcare System, Hollywood, Florida, USA
  4. 4Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, Florida, USA
  1. Correspondence to Dr Zhanju Liu, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China; liuzhanju88{at}126.com

Abstract

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 Mcpip1fl/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+Cx3cr1Cd163Mrc1Ly6c+) 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 Mcpip1ΔMye 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.

  • IBD basic research
  • immune response
  • mucosal immunology
  • gut immunology
  • macrophages

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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Footnotes

  • Twitter @zhu_ruixin

  • HL, CZ and WW contributed equally.

  • Contributors ZL conceived the study; HL, CZ, WW and ZL selected studies for inclusion, wrote the protocol and performed most experiments and statistical analyses; HC and RL bred the mice; RS and XG performed the immunostaining; GL and JL interpreted the data; QH, HG and XW contributed to the clinical data and specimens; RZ performed a bioinformatics analysis; JN and PEK provided myeloid cell-specific Mcpip1-deficient mice; HL, CZ and ZL drafted the manuscript. All authors approved the final draft.

  • Funding This work was funded by grants from the National Natural Science Foundation of China (91942312, 81630017).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.