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STAT1-mediated induction of Ly6c-expressing macrophages are involved in the pathogenesis of an acute colitis model

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Abstract

Background

The development of inflammatory bowel diseases is thought to be multifactorial, but the exact steps in pathogenesis are poorly understood. In this study, we investigated involvement of the activation of STAT1 signal pathway in the pathogenesis of an acute colitis model.

Methods

A dextran sulfate sodium-induced acute colitis model was established by using wild-type C57BL/6 mice and STAT1-deficient mice. Disease indicators such as body weight loss and clinical score, induction of cytokines, chemokines, and inflammatory cells were evaluated in the acute colitis model.

Results

Disease state was significantly improved in the acute colitis model using STAT1-deficient mice compared with wild-type mice. The induction of Ly6c-highly expressing cells in colorectal tissues was attenuated in STAT1-deficient mice. IL-6, CCL2, and CCR2 gene expressions in Ly6c-highly expressing cells accumulated in the inflamed colon tissues and were significantly higher than in Ly6c-intermediate-expressing cells, whereas TNF-α and IFN-α/β gene expression was higher in Ly6c-intermediate-expressing cells. Blockade of CCR2-mediated signaling significantly reduced the disease state in the acute colitis model.

Conclusions

Two different types of Ly6c-expressing macrophages are induced in the inflamed tissues through the IFN-α/β-STAT1-mediated CCL2/CCR2 cascade and this is associated with the pathogenesis such as onset, exacerbation, and subsequent chronicity of acute colitis.

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Acknowledgements

We thank Dr. Y. Ohno, Dr. N. Okada, and Dr. K. Sugiyama for their excellent and thoughtful advice on this study. This work was partially supported by a Grants-in-Aid for Scientific Research (C) (15K08416 to H.K.) and by a Grants-in-Aid for Scientific Research (B) (16H05409 to A.T.) from the Japan Society for the Promotion of Science (JSPS), the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (H.K.), the Japan Agency for Medical Research and Development (AMED) (H.K. and A.T.), and the Joint Research Program of the Institute for Genetic Medicine, Hokkaido University (S.H., M.T., and A.T.). We thank Kate Fox, DPhil, from Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan

    Shuhei Kii & Hidemitsu Kitamura

  2. Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Shuhei Kii, Nobuki Ichikawa, Tadashi Yoshida, Shigenori Homma & Akinobu Taketomi

  3. Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan

    Shinichi Hashimoto

  4. DNA Data Analysis Laboratory, National Institute of Genetics, Mishima, Japan

    Kazuho Ikeo

  5. Department of Surgical Pathology, Asahikawa Medical University, Asahikawa, Japan

    Mishie Tanino

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  1. Shuhei Kii
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Contributions

H.K. and A.T. conceived the project. H.K. designed the experiments. S.K. performed experiments and wrote the manuscript. S.K., S.H., K.I., M.T., and H.K. analyzed and interpreted the results. N.I., T.Y., S.H., and A.T. provided clinical samples and advice. M.T. and S.K. performed the histological analyses. A.T. generated and evaluated clinical data and guided the work.

Corresponding author

Correspondence to Hidemitsu Kitamura.

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Conflict of interest

The authors have no conflicts of interest to disclose.

Ethics approval statement for human and animal studies

Research protocols involving human subjects were approved by the institutional review board of Hokkaido University Graduate School of Medicine (14-043) and the Institute for Genetic Medicine (14-0004). Written informed consent was obtained from all patients. All procedures in this study were carried out in accordance with the relevant guidelines and regulations and according to the Declaration of Helsinki. All mouse experiments were approved by the Animal Ethics Committee of Hokkaido University (No. 14-0039, 19-0035, 19-0065) and were conducted in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the University.

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Kii, S., Kitamura, H., Hashimoto, S. et al. STAT1-mediated induction of Ly6c-expressing macrophages are involved in the pathogenesis of an acute colitis model. Inflamm. Res. 71, 1079–1094 (2022). https://doi.org/10.1007/s00011-022-01620-z

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