Abstract 4141686: Chromatin Remodeling Drives Immune-Fibroblast Cell Communication in Heart Failure

Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet the molecular mechanisms governing their crosstalk are poorly understood. In diseased organs, stress-induced changes in gene expression fuel maladaptive cell state transitions and pathological interaction between diverse cellular compartments. Although chronic fibroblast activation worsens dysfunction in the lung, liver, kidney, and heart, and exacerbates many cancers, the stress-sensing mechanisms initiating the transcriptional activation of fibroblasts are not well understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in infiltrating Cx3cr1 -positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancy in vivo in Cx3cr1 -positive cells identified a large enhancer proximal to Interleukin-1 beta ( Il1b) , and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controls expression of Il1b in disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factor MEOX1 , resulting in a profibrotic response in human cardiac fibroblasts. In vivo , antibody-mediated IL1B neutralization improved cardiac function and tissue fibrosis in heart failure. Mechanistically, systemic IL1B inhibition or targeted Il1b deletion in Cx3cr1 -positive cells prevented stress-induced expression of MEOX1 and inhibited fibroblast activation. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides mechanistic insights into how inflammation drives profibrotic cell states and presents new therapeutic strategies for heart disease and other chronic inflammatory disorders featuring maladaptive tissue remodeling.