| First Author | Davis FM | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 6 | PubMed ID | 33779682 |
| Mgi Jnum | J:314431 | Mgi Id | MGI:6724828 |
| Doi | 10.1084/jem.20201839 | Citation | Davis FM, et al. (2021) Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms. J Exp Med 218(6) |
| abstractText | Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. 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-beta regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-kappaB-mediated 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-induced 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. |
