Abstract
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-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB-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.
Original language | English |
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Article number | e20201839 |
Journal | Journal of Experimental Medicine |
Volume | 218 |
Issue number | 6 |
DOIs | |
State | Published - Jun 7 2021 |
Bibliographical note
Funding Information:This work is supported in part by National Institutes of Health grants R01-HL137919 (K.A. Gallagher) and F32-DK117545 (F.M. Davis), an American College of Surgeons resident fellowship (F.M. Davis), a Vascular and Endovascular Surgery Society resident research award (F.M. Davis), National Institutes of Health grants P30 AR075043 (J.E. Gudjonsson and L.C. Tsoi) and R01-AR069071 (J.E. Gudjonsson), and the Doris Duke Foundation (K.A. Gallagher).
Publisher Copyright:
© 2021 Rockefeller University Press. All rights reserved.
ASJC Scopus subject areas
- Medicine (all)