Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 6, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20201839
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Funding
- National Institutes of Health [R01-HL137919, F32-DK117545, P30 AR075043, R01-AR069071]
- American College of Surgeons resident fellowship
- Vascular and Endovascular Surgery Society resident research award
- Doris Duke Foundation
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JMJD3 plays a critical role in the pathogenesis of abdominal aortic aneurysms by regulating the inflammatory immune response in macrophages. Targeted inhibition of JMJD3 can reduce AAA expansion and attenuate macrophage-mediated inflammation, suggesting that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA.
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 NFxB-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.
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