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CD8 T cell-derived perforin regulates macrophage-mediated inflammation in a murine model of gout

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Abstract

Objectives

Gout is characterized by hyperuricemia and recurrent inflammatory episodes caused by intra-articular crystal deposition of monosodium urate (MSU). There is a clear relationship between gout and metabolic syndrome. Recent evidence indicates that perforin plays a role in regulating glucose homeostasis and provides protection in diet-induced non-alcoholic steatohepatitis models. However, the impact of perforin on immune inflammation in gout remains unclear.

Methods

We induced acute gout models in both wild-type (WT) mice and Prf1null mice by administering intra-articular injections of MSU crystals. We compared the ankle joint swelling and the histological score between the two groups. Furthermore, we investigated underlying mechanisms through in vitro co-culture experiments involving CD8 T cells and macrophages.

Results

In this study, Prf1null mice showed significantly more pronounced ankle swelling with increased inflammatory cell infiltrations compared with WT mice 24 h after local MSU injection. Moreover, MSU-induced Prf1null mice exhibited increased accumulation of CD8 T cells but not NK cells. Perforin-deficient CD8 T cells displayed reduced cytotoxicity towards bone marrow–derived M0 and M1 macrophages and promoted TNF-α secretion from macrophage.

Conclusions

Perforin from CD8 T cells limits joint inflammation in mice with acute gout by downregulating macrophage-mediated inflammation.

Key Points

• Perforin deficiency increased swelling in the ankle joints of mice upon MSU injection.

• Perforin deficiency is associated with increased immune cell recruitment and severe joint damage in gout.

• Perforin regulated CD8 T cell accumulation in gout and promoted CD8 T cell cytotoxicity towards M0 and M1 macrophages.

• CD8 T cell-derived perforin regulated pro-inflammatory cytokine secretion of macrophage.

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Data availability

Data are available upon reasonable request. Requests for data should be directed to the principal investigator, Dr. Yanying Liu (Liuyanying6850@126.com). Additionally, one study author has full access to all the data in the study and takes responsibility for its integrity and the data analysis.

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Authors and Affiliations

  1. Department of Rheumatology and Immunology, Beijing Friendship Hospital, Capital Medical University, 95th, Yongan Road, Beijing, 100050, China

    Tianqi Wang, Mingzhu Zhou, Hang Zhou, Xia Zhang, Huilan Liu, Mingxin Bai, Yuetong Xu, Fan Yang, Fengyunzhi Zhu, Qiyuan Hao, Tong Zhang, Shuju Song, Haiyu Qi & Yanying Liu

  2. Department of Infectious Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China

    Chunpan Zhang

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  1. Tianqi Wang
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  2. Chunpan Zhang
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  3. Mingzhu Zhou
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  4. Hang Zhou
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  5. Xia Zhang
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  13. Shuju Song
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  15. Yanying Liu
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Contributions

Yanying Liu and Tianqi Wang contributed to study conception and design. All authors contributed to experimental studies. Yanying Liu and Tianqi Wang contributed to analysis of data and drafting the manuscript. All authors had read and approved the final version to be published.

Corresponding author

Correspondence to Yanying Liu.

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Wang, T., Zhang, C., Zhou, M. et al. CD8 T cell-derived perforin regulates macrophage-mediated inflammation in a murine model of gout. Clin Rheumatol (2024). https://doi.org/10.1007/s10067-024-06964-x

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