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During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte\/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-\u03b2 regulates Jmjd3 expression via JAK\/STAT and that JMJD3 induces NF-\u03baB\u2013mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f\/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II\u2013induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.<\/jats:p>","DOI":"10.1084\/jem.20201839","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T02:23:18Z","timestamp":1613787798000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":157,"title":["Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5847-8993","authenticated-orcid":true,"given":"Frank M.","family":"Davis","sequence":"first","affiliation":[{"name":"Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 1"},{"name":"Department Microbiology and Immunology, University of Michigan, Ann Arbor, MI 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