TAK1 drives inflammatory fibroblast acquisition and shapes myocardial infarction responses in male mice

Organ function depends on communication among cell types to coordinate tissue growth and repair. Although fibroblasts are critical to this process, their role in regulating inflammatory responses to injury remain ambiguous. Here, we show that transforming growth factor β-activated kinase 1 (TAK1) is a gatekeeper of an inflammatory cardiac fibroblast phenotype. In cardiac fibroblasts, TAK1 signaling controls the acquisition of defining features of inflammatory fibroblasts, including chemokine and cytokine synthesis, lipid mediator production, metalloproteinase activity, and damage-associated molecular pattern recognition. Moreover, TAK1 propagates IL-1β and TNF-α signaling, but not TGF-β-SMAD signaling, regulating inflammatory programs by increasing chemokine secretion while decreasing lipid mediator production. Fibroblast-specific TAK1 deletion decreases neutrophil chemotaxis in vitro and immune cell recruitment after myocardial infarction in vivo, which is associated with improved cardiac remodeling and function in male mice. These results further resolve the nature and function of inflammatory fibroblasts in cardiac responses to injury and identify TAK1 signaling as a critical mediator. After a heart attack, fibroblasts help coordinate inflammation and repair, but the signals controlling this response are unclear. Here, the authors show that TAK1 drives an inflammatory fibroblast state that worsens remodeling after myocardial infarction in male mice.