Chromatin Remodeling Drives Immune-Fibroblast Cell Communication in Heart Failure (scRNA-Seq)

Chronic inflammation and tissue fibrosis are common stress responses that worsen organ function, yet their crosstalk is poorly understood. Here, we show that conditional deletion of the transcription co-activator Brd4 in Cx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. We identified a specific BRD4-occupied enhancer in Cx3cr1-positive cells that controls expression of Interleukin-1 beta (Il1b), and show that secreted IL1B activates a p65/RELA-dependent enhancer downstream of MEOX1, driving a profibrotic response in human cardiac fibroblasts. In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression of MEOX1, inhibited fibroblast activation, and improved cardiac function in heart failure. The elucidation of BRD4-dependent crosstalk between a specific immune cell subset and fibroblasts through IL1B provides new therapeutic strategies for heart disease and other disorders of chronic inflammation and maladaptive tissue remodeling. Single cell or nuclei RNAseq from adult heart in the context of BET bromodomain inhibition, BRD4 genetic deletion and neutralization of the cytokine IL1B