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ALOX5 drives the pyroptosis of CD4 + T cells and tissue inflammation in rheumatoid arthritis.

Hao CaiJianhua ZhangHua XuWeiwei SunWeijie WuChen DongPing ZhouChengbin XueYunyi NanYingchen NiXinyuan WuZhi-Feng GuMin-Hao ChenYouhua Wang
Published in: Science signaling (2024)
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.
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