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.
Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms
Disclosures: The authors declare no competing interests exist.
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Frank M. Davis, Lam C. Tsoi, William J. Melvin, Aaron denDekker, Rachael Wasikowski, Amrita D. Joshi, Sonya Wolf, Andrea T. Obi, Allison C. Billi, Xianying Xing, Christopher Audu, Bethany B. Moore, Steven L. Kunkel, Alan Daugherty, Hong S. Lu, Johann E. Gudjonsson, Katherine A. Gallagher; Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms. J Exp Med 7 June 2021; 218 (6): e20201839. doi: https://doi.org/10.1084/jem.20201839
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