Wang Tianqi, Zhang Chunpan, Zhou Mingzhu, Zhou Hang, Zhang Xia, Liu Huilan, Bai Mingxin, Xu Yuetong, Yang Fan, Zhu Fengyunzhi, Hao Qiyuan, Zhang Tong, Song Shuju, Qi Haiyu, Liu Yanying
Department of Rheumatology and Immunology, Beijing Friendship Hospital, Capital Medical University, 95th, Yongan Road, Beijing, 100050, China.
Department of Infectious Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Clin Rheumatol. 2024 Jun;43(6):2027-2034. doi: 10.1007/s10067-024-06964-x. Epub 2024 Apr 16.
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.
We induced acute gout models in both wild-type (WT) mice and Prf1 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.
In this study, Prf1 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 Prf1 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.
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.
痛风的特征是高尿酸血症以及由尿酸钠（MSU）关节内晶体沉积引起的反复发作的炎症。痛风与代谢综合征之间存在明确的关联。最近的证据表明，穿孔素在调节葡萄糖稳态中起作用，并在饮食诱导的非酒精性脂肪性肝炎模型中提供保护。然而，穿孔素对痛风免疫炎症的影响仍不清楚。
我们通过关节内注射MSU晶体在野生型（WT）小鼠和Prf1小鼠中诱导急性痛风模型。我们比较了两组之间的踝关节肿胀和组织学评分。此外，我们通过涉及CD8 T细胞和巨噬细胞的体外共培养实验研究了潜在机制。
在本研究中，与局部注射MSU 24小时后的WT小鼠相比，Prf1小鼠的踝关节肿胀明显更明显，炎症细胞浸润增加。此外，MSU诱导的Prf1小鼠表现出CD8 T细胞而非NK细胞的积累增加。穿孔素缺陷的CD8 T细胞对骨髓来源的M0和M1巨噬细胞的细胞毒性降低，并促进巨噬细胞分泌TNF-α。
CD8 T细胞的穿孔素通过下调巨噬细胞介导的炎症来限制急性痛风小鼠的关节炎症。要点•穿孔素缺乏会增加MSU注射后小鼠踝关节的肿胀。•穿孔素缺乏与痛风中免疫细胞募集增加和严重关节损伤有关。•穿孔素调节痛风中CD8 T细胞的积累，并促进CD8 T细胞对M0和M1巨噬细胞的细胞毒性。•CD8 T细胞来源的穿孔素调节巨噬细胞促炎细胞因子的分泌。
