Chromatin remodelling drives immune cell–fibroblast communication in heart failure

Michael Alexanian (), Arun Padmanabhan, Tomohiro Nishino, Joshua G. Travers, Lin Ye, Angelo Pelonero, Clara Youngna Lee, Nandhini Sadagopan, Yu Huang, Kirsten Auclair, Ada Zhu, Yuqian An, Christina A. Ekstrand, Cassandra Martinez, Barbara Gonzalez Teran, Will R. Flanigan, Charis Kee-Seon Kim, Koya Lumbao-Conradson, Zachary Gardner, Li Li, Mauro W. Costa, Rajan Jain, Israel Charo, Alexis J. Combes, Saptarsi M. Haldar, Katherine S. Pollard, Ronald J. Vagnozzi, Timothy A. McKinsey, Pawel F. Przytycki and Deepak Srivastava
Additional contact information
Michael Alexanian: Gladstone Institutes
Arun Padmanabhan: Gladstone Institutes
Tomohiro Nishino: Gladstone Institutes
Joshua G. Travers: University of Colorado Anschutz Medical Campus
Lin Ye: Gladstone Institutes
Angelo Pelonero: Gladstone Institutes
Clara Youngna Lee: Gladstone Institutes
Nandhini Sadagopan: Gladstone Institutes
Yu Huang: Gladstone Institutes
Kirsten Auclair: Gladstone Institutes
Ada Zhu: Gladstone Institutes
Yuqian An: Gladstone Institutes
Christina A. Ekstrand: University of California
Cassandra Martinez: Gladstone Institutes
Barbara Gonzalez Teran: Gladstone Institutes
Will R. Flanigan: Gladstone Institutes
Charis Kee-Seon Kim: Gladstone Institutes
Koya Lumbao-Conradson: University of Colorado Anschutz Medical Campus
Zachary Gardner: University of Pennsylvania
Li Li: University of Pennsylvania
Mauro W. Costa: Gladstone Institutes
Rajan Jain: University of Pennsylvania
Israel Charo: Gladstone Institutes
Alexis J. Combes: University of California
Saptarsi M. Haldar: Gladstone Institutes
Katherine S. Pollard: Gladstone Institutes
Ronald J. Vagnozzi: University of Colorado Anschutz Medical Campus
Timothy A. McKinsey: University of Colorado Anschutz Medical Campus
Pawel F. Przytycki: Gladstone Institutes
Deepak Srivastava: Gladstone Institutes

Nature, 2024, vol. 635, issue 8038, 434-443

Abstract: Abstract Chronic inflammation and tissue fibrosis are common responses that worsen organ function, yet the molecular mechanisms governing their cross-talk are poorly understood. In diseased organs, stress-induced gene expression changes fuel maladaptive cell state transitions1 and pathological interaction between cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lungs, liver, kidneys and heart, and exacerbates many cancers2, the stress-sensing mechanisms initiating transcriptional activation of fibroblasts are poorly understood. Here we show that conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1+ macrophages ameliorates heart failure in mice and significantly reduces fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1+ cells identified a large enhancer proximal to interleukin-1β (IL-1β, encoded by Il1b), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1β activated a fibroblast RELA-dependent (also known as p65) enhancer near the transcription factor MEOX1, resulting in a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL-1β neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1β inhibition or targeted Il1b deletion in Cx3cr1+ cells prevented stress-induced Meox1 expression and fibroblast activation. The elucidation of BRD4-dependent cross-talk between a specific immune cell subset and fibroblasts through IL-1β reveals how inflammation drives profibrotic cell states and supports strategies that modulate this process in heart disease and other chronic inflammatory disorders featuring tissue remodelling.

Date: 2024
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DOI: 10.1038/s41586-024-08085-6

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