Pyroptosis, an inflammatory form of programmed cell death, is linked to the pathology of rheumatoid arthritis (RA). Here, we investigated the molecular mechanism underlying pyroptosis in T cells isolated from patients with RA. Compared with healthy individuals, patients with RA had more pyroptotic CD4 + T cells in blood and synovia, which correlated with clinical measures of disease activity. Moreover, the mRNA expression and protein abundance of arachidonate 5-lipoxygenase (ALOX5), which converts arachidonic acid to leukotriene A 4 (LTA 4 ), were increased in CD4 + T cells from patients with RA and, among patients with RA, were lowest in those in clinical remission. Knockdown or pharmacological inhibition of ALOX5 suppressed CD4 + T cell pyroptosis and improved symptoms in two rodent models of RA. Mechanistically, the increase in ALOX5 activity in RA CD4 + T cells enhanced the production of the LTA 4 derivative LTB 4 , which stimulated Ca 2+ influx through ORAI3 channels, leading to the activation of NLRP3 inflammasomes and pyroptosis. Our findings reveal a role for ALOX5 in RA and provide a molecular basis for further exploring the clinical utility of ALOX5 inhibition in RA and for using ALOX5 as a biomarker to distinguish active disease and remission in RA.

中文翻译：

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ALOX5 驱动类风湿性关节炎中 CD4 + T 细胞焦亡和组织炎症

焦亡是程序性细胞死亡的一种炎症形式，与类风湿性关节炎 (RA) 的病理有关。在这里，我们研究了从 RA 患者分离的 T 细胞焦亡的分子机制。与健康个体相比，RA患者有更多的焦亡CD4+血液和滑液中的 T 细胞，与疾病活动的临床测量相关。此外，将花生四烯酸转化为白三烯 A 的花生四烯酸 5-脂氧合酶 (ALOX5) 的 mRNA 表达和蛋白质丰度4（长期协议4), CD4 增加+RA 患者以及 RA 患者中的 T 细胞在临床缓解患者中最低。敲低或药物抑制 ALOX5 可抑制 CD4+两种 RA 啮齿动物模型中的 T 细胞焦亡和症状改善。从机制上讲，RA CD4 中 ALOX5 活性的增加+T 细胞增强 LTA 的产生4衍生LTB4, 刺激了 Ca2+通过 ORAI3 通道流入，导致 NLRP3 炎性体激活和细胞焦亡。我们的研究结果揭示了 ALOX5 在 RA 中的作用，并为进一步探索 ALOX5 抑制在 RA 中的临床效用以及使用 ALOX5 作为区分 RA 活动性疾病和缓解期的生物标志物提供了分子基础。