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However, the underlying pathological mechanisms of the 5\u2010HT system in atherosclerosis remain unclear. The 5\u2010HT<jats:sub>2B<\/jats:sub> receptor (5\u2010HT2BR), which establishes a positive feedback loop with 5\u2010HT, has been identified as a contributor to pathophysiological processes in various vascular disorders. In this study, we investigated the immunological impact of 5\u2010HT2BR in atherosclerosis\u2010prone apolipoprotein E\u2010deficient (ApoE<jats:sup>\u2212\/\u2212<\/jats:sup>) mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Plasma levels of 5\u2010HT were measured in mice using an ELISA kit. Atherosclerotic plaque formation, macrophage infiltration and inflammatory signalling were assessed in ApoE<jats:sup>\u2212\/\u2212<\/jats:sup> mice by employing both pharmacological inhibition and genetic deficiency of 5\u2010HT2BR. Inflammasome activation was elucidated using peritoneal macrophages isolated from 5\u2010HT2BR\u2010deficient mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>An upregulation of 5\u2010HT2BR expression was observed in the aortas of ApoE<jats:sup>\u2212\/\u2212<\/jats:sup> 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\u2010HT2BR. Additionally, a significant reduction in atherosclerotic plaque size was achieved through bone marrow reconstitution with 5\u2010HT2BR\u2010deficient cells. 5\u2010HT2BR\u2010deficient macrophages showed attenuated interferon (IFN) signalling, NLRP3 inflammasome activation, and interleukin\u20101\u03b2 release. Moreover, macrophages primed with 5\u2010HT2BR deficiency displayed an anti\u2010inflammatory phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>These findings support the hypothesis that 5\u2010HT2BR in macrophages plays a causal role in the development of atherosclerosis, revealing a novel perspective for potential therapeutic strategies in atherosclerosis\u2010related diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17315","type":"journal-article","created":{"date-parts":[[2024,9,4]],"date-time":"2024-09-04T23:35:40Z","timestamp":1725492940000},"page":"4894-4910","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Deficiency of 5\u2010HT<sub>2B<\/sub> receptors alleviates atherosclerosis by regulating macrophage phenotype through inhibiting interferon signalling"],"prefix":"10.1111","volume":"182","author":[{"given":"Yahan","family":"Liu","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Sciences, School of Basic Medical Sciences Peking University Health Science Center; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhipeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences, School of Basic Medical Sciences Peking University Health Science Center; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Fang","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences, School of Basic Medical Sciences Peking University Health Science Center; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaohua","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences, School of Basic Medical Sciences Peking University Health 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