| Autor: |
Michael Alexanian, Arun Padmanabhan, Tomohiro Nishino, Joshua G. Travers, Lin Ye, Clara Youngna Lee, Nandhini Sadagopan, Yu Huang, Angelo Pelonero, Kirsten Auclair, Ada Zhu, Barbara Gonzalez Teran, Will Flanigan, Charis Kee-Seon Kim, Koya Lumbao-Conradson, Mauro Costa, Rajan Jain, Israel Charo, Saptarsi M. Haldar, Katherine S. Pollard, Ronald J. Vagnozzi, Timothy A. McKinsey, Pawel F. Przytycki, Deepak Srivastava |
| Rok vydání: |
2023 |
| DOI: |
10.1101/2023.01.06.522937 |
| Popis: |
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 of 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-activatorBrd4inCx3cr1-positive myeloid cells ameliorates heart failure and is associated with a dramatic reduction in fibroblast activation. Analysis of single-cell chromatin accessibility and BRD4 occupancyin vivoinCx3cr1-positive cells identified a large enhancer proximal toInterleukin-1 beta (Il1b), and a series of CRISPR deletions revealed the precise stress-dependent regulatory element that controlled expression ofIl1bin disease. Secreted IL1B functioned non-cell autonomously to activate a p65/RELA-dependent enhancer near the transcription factorMEOX1, resulting in a profibrotic response in human cardiac fibroblasts.In vivo, antibody-mediated IL1B neutralization prevented stress-induced expression ofMEOX1, 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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