Deficiency of 5‐HT2B receptors alleviates atherosclerosis by regulating macrophage phenotype through inhibiting interferon signalling.

Background and Purpose Experimental Approach Key Results Conclusion and Implications Elevated levels of 5‐HT have been correlated with coronary artery disease and cardiac events, suggesting 5‐HT is a potential novel factor in the development of atherosclerotic cardiovascular disease. However, the underlying pathological mechanisms of the 5‐HT system in atherosclerosis remain unclear. The 5‐HT2B receptor (5‐HT2BR), which establishes a positive feedback loop with 5‐HT, has been identified as a contributor to pathophysiological processes in various vascular disorders. In this study, we investigated the immunological impact of 5‐HT2BR in atherosclerosis‐prone apolipoprotein E‐deficient (ApoE−/−) mice.Plasma levels of 5‐HT were measured in mice using an ELISA kit. Atherosclerotic plaque formation, macrophage infiltration and inflammatory signalling were assessed in ApoE−/− mice by employing both pharmacological inhibition and genetic deficiency of 5‐HT2BR. Inflammasome activation was elucidated using peritoneal macrophages isolated from 5‐HT2BR‐deficient mice.An upregulation of 5‐HT2BR expression was observed in the aortas of ApoE−/− mice, exhibiting a strong correlation with the presence of macrophages in plaques. Atherosclerosis was attenuated in mice through pharmacological inhibition and genetic deficiency of 5‐HT2BR. Additionally, a significant reduction in atherosclerotic plaque size was achieved through bone marrow reconstitution with 5‐HT2BR‐deficient cells. 5‐HT2BR‐deficient macrophages showed attenuated interferon (IFN) signalling, NLRP3 inflammasome activation, and interleukin‐1β release. Moreover, macrophages primed with 5‐HT2BR deficiency displayed an anti‐inflammatory phenotype.These findings support the hypothesis that 5‐HT2BR in macrophages plays a causal role in the development of atherosclerosis, revealing a novel perspective for potential therapeutic strategies in atherosclerosis‐related diseases. [ABSTRACT FROM AUTHOR]