IL-21R blockade reduces inflammation and atherosclerosis in LDL receptor deficient mice.

BACKGROUND: Interleukin-21 (IL-21) is a pro-inflammatory cytokine involved in the regulation of both innate and adaptive immune responses and has been associated with atherosclerotic cardiovascular disease (ASCVD). However, the exact role of IL-21/IL-21R signaling in atherosclerosis and the therapeutic potential of targeting this axis remain unclear. METHODS AND RESULTS: scRNAseq of human carotid plaques revealed that IL-21R is highly expressed on Tregs, with increased levels in women versus men and in fibrous plaques versus other phenotypes. In line with these findings, we showed that IL-21R blockade using an anti-IL-21R monoclonal antibody in young (20 weeks) Ldlr-/- mice increased Treg frequencies in secondary lymphoid organs (SLOs), accompanied by increased serum IL-10. Moreover, we observed reduced pro-inflammatory monocytes in the aorta and spleen of anti-IL-21R-treated mice. This contributed to a reduction of 38% in atherosclerotic plaque area (p < 0.05) and 61% less macrophage content (p = 0.053) upon IL-21R blockade. Furthermore, scRNAseq analysis of the spleen and aorta of female Ldlr-/- mice demonstrated an age-associated increase in Il21/Il21r expression within Tregs and Tfh cells. Subsequent IL-21R blockade in aged (88 weeks) Ldlr-/- mice with well-established plaques reduced inflammation, as shown by an increase in aortic Tregs, elevated Foxp3 expression in Tregs from SLOs and reduced pro-inflammatory monocytes. Additionally, anti-IL-21R-treated aged mice showed reduced Tfh cells, as well as reduced plasmablasts and plasma cells. CONCLUSIONS: Collectively, we show that IL-21R blockade attenuates plaque initiation, promotes atheroprotective Tregs, inhibits pro-inflammatory monocytes and impairs Tfh-B cell dynamics upon aging, representing a promising novel therapeutic strategy to combat ASCVD.