| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Science Signaling; 2/27/2024, Vol. 17 Issue 825, p1-17, 17p |
| Abstrakt: |
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 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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