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ALOX5 drives the pyroptosis of CD4+ T cells and tissue inflammation in rheumatoid arthritis.
- Source :
- Science Signaling; 2/27/2024, Vol. 17 Issue 825, p1-17, 17p
- Publication Year :
- 2024
-
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<superscript>+</superscript> 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<subscript>4</subscript> (LTA<subscript>4</subscript>), were increased in CD4<superscript>+</superscript> 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<superscript>+</superscript> T cell pyroptosis and improved symptoms in two rodent models of RA. Mechanistically, the increase in ALOX5 activity in RA CD4<superscript>+</superscript> T cells enhanced the production of the LTA<subscript>4</subscript> derivative LTB<subscript>4</subscript>, which stimulated Ca<superscript>2+</superscript> 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<superscript>+</superscript> 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<superscript>+</superscript> T cells drove pyroptosis in these cells, which correlated with the clinical severity of RA. Leukotrienes generated by ALOX5 stimulated Ca<superscript>2+</superscript> influx through ORAI3 channels that led to inflammasome activation and pyroptosis. The FDA-approved ALOX5 inhibitor zileuton suppressed CD4<superscript>+</superscript> 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]
- Subjects :
- T cells
PYROPTOSIS
RHEUMATOID arthritis
APOPTOSIS
BLOOD cells
DISEASE remission
Subjects
Details
- Language :
- English
- ISSN :
- 19450877
- Volume :
- 17
- Issue :
- 825
- Database :
- Complementary Index
- Journal :
- Science Signaling
- Publication Type :
- Academic Journal
- Accession number :
- 175701727
- Full Text :
- https://doi.org/10.1126/scisignal.adh1178