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- Title
ALOX5 drives the pyroptosis of CD4<sup>+</sup> T cells and tissue inflammation in rheumatoid arthritis.
- Authors
Cai, Hao; Zhang, Jianhua; Xu, Hua; Sun, Weiwei; Wu, Weijie; Dong, Chen; Zhou, Ping; Xue, Chengbin; Nan, Yunyi; Ni, Yingchen; Wu, Xinyuan; Gu, Zhifeng; Chen, Minhao; Wang, Youhua
- Abstract
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 A4 (LTA4), 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 LTA4 derivative LTB4, which stimulated Ca2+ 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. Editor's summary: Pyroptosis of CD4+ T cells is associated with synovial inflammation in rheumatoid arthritis (RA). Cai et al. found that increased abundance of the leukotriene biosynthetic enzyme ALOX5 in circulating and synovium-infiltrating CD4+ T cells drove pyroptosis in these cells, which correlated with the clinical severity of RA. Leukotrienes generated by ALOX5 stimulated Ca2+ influx through ORAI3 channels that led to inflammasome activation and pyroptosis. The FDA-approved ALOX5 inhibitor zileuton suppressed CD4+ T cell pyroptosis and reduced joint inflammation in rodent models of RA, suggesting ALOX5 as a potential therapeutic target in RA. —Annalisa M. VanHook
- Subjects
UNITED States. Food &; Drug Administration; T cells; PYROPTOSIS; RHEUMATOID arthritis; APOPTOSIS; BLOOD cells; DISEASE remission
- Publication
Science Signaling, 2024, Vol 17, Issue 825, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.adh1178