Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms

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

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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 languageEnglish
Article numbere20201839
JournalJournal of Experimental Medicine
Volume218
Issue number6
DOIs
StatePublished - Jun 7 2021

Bibliographical note

Publisher Copyright:
© 2021 Rockefeller University Press. All rights reserved.

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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