TGFβ-activated kinase 1 signaling controls acquisition of the inflammatory fibroblast phenotype and regulates cardiac remodeling after myocardial infarction.

Organ health and function depend on communication between cell types to coordinate tissue growth and repair. Recent studies have indicated that fibroblasts are critical to this process; however, their role in regulating inflammatory responses to injury have remained ambiguous. Here, we demonstrate that transforming growth factor β-activated kinase 1 (TAK1) is a gatekeeper of the inflammatory cardiac fibroblast phenotype. We find that TAK1 propagates IL-1β and TNF-α signaling in cardiac fibroblasts and coordinates the synthesis and secretion of chemokines as well as inflammatory and pro-resolving lipid mediators. Deletion of TAK1 in fibroblasts decreased immune cell recruitment after MI, which was associated with improved cardiac structural and functional remodeling in male mice. Nevertheless, we found the effects of TAK1 deletion to be sexually dimorphic in nature, providing support to the idea that the protected phenotype of the female sex may be based in disparate immune and inflammatory responses. Moreover, TAK1 signaling controlled the acquisition of novel markers of the inflammatory fibroblast phenotype, having a biological basis in redox stress, chemokine and lipid mediator biosynthesis, metalloproteinase activity, and damage-associated molecular pattern recognition. Collectively, these results further resolve the nature and function of inflammatory cardiac fibroblasts in cardiac responses to injury and identify TAK1 signaling in fibroblasts as a potential target for therapy.