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

Anti-Rat CD28 ; Anti-Rat CD3 ; 10313 ; 05113 ;

Sci Signal. 2024 Feb 27;17(825):eadh1178. doi: 10.1126/scisignal.adh1178. Epub 2024 Feb 27.

Hao Cai ¹, Jianhua Zhang ¹, Hua Xu ¹, Weiwei Sun ¹, Weijie Wu ¹, Chen Dong ², Ping Zhou ³, Chengbin Xue ⁴, Yunyi Nan ¹, Yingchen Ni ¹, Xinyuan Wu ¹, Zhifeng Gu ², Minhao Chen ¹, Youhua Wang ¹

Affiliations expand

• PMID: 38412254
• DOI: 10.1126/scisignal.adh1178

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.