2. Academic Validation
  3. Chromatin remodelling drives immune cell-fibroblast communication in heart failure

Chromatin remodelling drives immune cell-fibroblast communication in heart failure

  • Nature. 2024 Oct 23. doi: 10.1038/s41586-024-08085-6.
Michael Alexanian # 1 2 3,  Arun Padmanabhan # 4 5 6 7,  Tomohiro Nishino 4 5,  Joshua G Travers 8,  Lin Ye 4 5,  Angelo Pelonero 4 5,  Clara Youngna Lee 4 5 6,  Nandhini Sadagopan 4 5 6,  Yu Huang 4 5,  Kirsten Auclair 4 5,  Ada Zhu 4 5,  Yuqian An 4 5,  Christina A Ekstrand 9 10,  Cassandra Martinez 4 5,  Barbara Gonzalez Teran 4 5,  Will R Flanigan 4 11,  Charis Kee-Seon Kim 4 5,  Koya Lumbao-Conradson 8,  Zachary Gardner 12 13 14 15,  Li Li 12 13 14 15,  Mauro W Costa 4 5,  Rajan Jain 12 13 14 15,  Israel Charo 4,  Alexis J Combes 9 10 16,  Saptarsi M Haldar 4 6 17,  Katherine S Pollard 4 7 18 19 20,  Ronald J Vagnozzi 8,  Timothy A McKinsey 8,  Pawel F Przytycki 4 21,  Deepak Srivastava 4 5 22 23
Affiliations

Affiliations

  • 1 Gladstone Institutes, San Francisco, CA, USA. michael.alexanian@gladstone.ucsf.edu.
  • 2 Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA. michael.alexanian@gladstone.ucsf.edu.
  • 3 Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. michael.alexanian@gladstone.ucsf.edu.
  • 4 Gladstone Institutes, San Francisco, CA, USA.
  • 5 Roddenberry Center for Stem Cell Biology at Gladstone Institutes, San Francisco, CA, USA.
  • 6 Department of Medicine, Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA.
  • 7 Chan Zuckerberg Biohub San Francisco, San Francisco, CA, USA.
  • 8 Department of Medicine, Division of Cardiology and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • 9 CoLabs initiative, University of California, San Francisco, CA, USA.
  • 10 ImmunoX initiative, University of California, San Francisco, CA, USA.
  • 11 UC Berkeley-UCSF Joint Program in Bioengineering, Berkeley, CA, USA.
  • 12 Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 13 Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA.
  • 14 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 15 Department of Cell Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 16 Department of Pathology, University of California, San Francisco, CA, USA.
  • 17 Amgen Research, Cardiometabolic Disorders, South San Francisco, CA, USA.
  • 18 Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, CA, USA.
  • 19 Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
  • 20 Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
  • 21 Faculty of Computing & Data Sciences, Boston University, Boston, MA, USA.
  • 22 Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
  • 23 Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
  • # Contributed equally.
PMID: 39443808 DOI: 10.1038/s41586-024-08085-6
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.

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