Chromatin remodelling drives immune cell-fibroblast communication in heart failure
成果类型：
Article
署名作者：
Alexanian, Michael; Padmanabhan, Arun; Nishino, Tomohiro; Travers, Joshua G.; Ye, Lin; Pelonero, Angelo; Lee, Clara Youngna; Sadagopan, Nandhini; Huang, Yu; Auclair, Kirsten; Zhu, Ada; An, Yuqian; Ekstrand, Christina A.; Martinez, Cassandra; Teran, Barbara Gonzalez; Flanigan, Will R.; Kim, Charis Kee-Seon; Lumbao-Conradson, Koya; Gardner, Zachary; Li, Li; Costa, Mauro W.; Jain, Rajan; Charo, Israel; Combes, Alexis J.; Haldar, Saptarsi M.; Pollard, Katherine S.; Vagnozzi, Ronald J.; Mckinsey, Timothy A.; Przytycki, Pawel F.; Srivastava, Deepak
署名单位：
University of California System; University of California San Francisco; The J David Gladstone Institutes; University of California System; University of California San Francisco; The J David Gladstone Institutes; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Chan Zuckerberg Initiative (CZI); University of Colorado System; University of Colorado Anschutz Medical Campus; University of Colorado System; University of Colorado Anschutz Medical Campus; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California Berkeley; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Boston University; University of California System; University of California San Francisco
刊物名称：
Nature
ISSN/ISSBN：
0028-5219
DOI：
10.1038/s41586-024-08085-6
发表日期：
2024-11-14
关键词：
摘要：
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-1 beta (IL-1 beta, encoded by Il1b), and a series of CRISPR-based deletions revealed the precise stress-dependent regulatory element that controls Il1b expression. Secreted IL-1 beta 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-1 beta neutralization improved cardiac function and tissue fibrosis in heart failure. Systemic IL-1 beta 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-1 beta 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. Conditional deletion of the transcriptional co-activator Brd4 in infiltrating Cx3cr1+ mouse macrophages ameliorates heart failure and substantially reduces fibroblast activation.