Chronic inflammation and tissue fibrosis are prevalent pathological responses that adversely affect organ function. However, the mechanisms governing intercellular interactions during these processes remain incompletely understood. In diseased organs, stress-induced gene expression promotes transitions between maladaptive cellular states and pathological interactions across cellular compartments. Notably, persistent fibroblast activation is known to aggravate dysfunction in organs such as the lungs, liver, kidneys, and heart, while also contributing to the progression of numerous cancers. Despite these findings, our comprehension of the stress-sensing mechanisms that initiate the transcriptional activation of fibroblasts remains limited.
Michael Alexanian and colleagues’ conducted experiments using cell isolation and ATAC-seq (Assay for Transposase-Accessible Chromatin Using Sequencing) techniques on mice to gain deeper insights into immune cell-fibroblast interactions. The study aimed to uncover the molecular mechanisms underlying communication between immune cells and fibroblasts in the context of heart failure. By integrating single-cell genomic analysis, small molecules, and genetic perturbation approaches, the researchers identified a fundamental mechanism by which pathological cellular communication in stressed organs drives human disease.
The study revealed that conditional deletion of the transcriptional coactivator BRD4 in infiltrating Cx3cr1+ macrophages alleviated heart failure in mice and significantly reduced fibroblast activation. In vivo single-cell chromatin accessibility and BRD4 binding analyses in Cx3cr1+ cells identified a major enhancer region proximal to interleukin-1β (IL-1β). CRISPR-based deletions further uncovered stress-associated regulatory elements controlling Il-1b expression.
The secreted IL-1β was shown to elicit a profibrotic response in human cardiac fibroblasts by activating a RELA (also known as p65)-dependent enhancer near the transcription factor MEOX1. In vivo studies demonstrated that antibody-mediated neutralization of IL-1β improved cardiac function and reduced tissue fibrosis in heart failure models. Additionally, systemic inhibition of IL-1β or targeted deletion of Il1b in Cx3cr1+ cells prevented stress-induced MEOX1 expression and fibroblast activation.
This groundbreaking study advances our understanding of the cellular and molecular progression of chronic inflammation and tissue fibrosis, shedding light on the role of immune cell-fibroblast interactions in disease. The researchers demonstrated that BRD4, IL-1β, and MEOX1 play critical roles in heart failure and that deletion of BRD4 in Cx3cr1+ macrophages or suppression of IL-1β reduced fibroblast activation and tissue fibrosis, thereby improving cardiac function.
In conclusion, the findings of this study provide potential therapeutic targets not only for heart failure but also for other chronic inflammation-related diseases, organ pathologies, and cancers. Furthermore, a deeper understanding of the mechanisms regulating stress-induced gene expression and fibroblast activation could pave the way for the development of personalized treatments, leading to more precise and effective therapies for these conditions.
Author: Semiha Nur Kavas
Editor: Fatma Duran
Reference: Alexanian, M., Padmanabhan, A., Nishino, T. et al. Chromatin remodelling drives immune cell–fibroblast communication in heart failure. Nature 635, 434–443 (2024). https://doi.org/10.1038/s41586-024-08085-6