TAK1 signaling is a gatekeeper of the inflammatory fibroblast phenotype and regulates cardiac remodeling after myocardial infarction

Introduction: Cardiac fibroblasts, known for their reactivity to pro-inflammatory stimuli, are increasingly recognized as key mediators of inflammation. TGF-β activated kinase 1 (TAK1) has been identified to integrate diverse inflammatory signals, but its role in fibroblast biology and myocardial remodeling remains unclear. The goal of this study was to determine the role of fibroblast-TAK1 signaling on acquisition of an inflammatory phenotype and in post-myocardial infarction (MI) repair and remodeling. We hypothesize that TAK1 signaling integrates inflammatory signals to promote cardiac fibroblast activation, which regulates inflammation and remodeling after MI. Methods and Results: We used a fibroblast-specific model for TAK1 knockdown, i.e. Col1a2-Cre ERT TAK1 fl/fl mice, and littermate controls to determine how TAK1 influences remodeling after permanent coronary ligation. Deletion of TAK1 in fibroblasts in vivo prior to MI improved functional outcomes and reduced fibrosis 28 days post-MI in male mice (n=9-14/group; p<0.05). Interestingly, the female cohort experienced greater rates of mortality in TAK1 deleted mice (52.0% vs 22.7%; n=22-25/group). Flow cytometric evaluation of immune cells in the hearts showed that fibroblast-TAK1 deletion reduced CD45 pos leukocytes, neutrophils, and Ly6C low patrolling monocytes acutely post-MI (n=6-13/group; p<0.05). To determine how TAK1 may regulate the pro-inflammatory phenotype, isolated cardiac fibroblasts from TAK1 fl/fl mice were pretreated with Ad-CMV-iCre and stimulated with TGFβ, TNFα, or IL-1β. Notably, TAK1 deletion suppressed TNFα and IL-1β-dependent p-p38, p-JNK, and NFκB signaling (n=5/group; p<0.05). Bulk RNAseq analysis further revealed that TAK1 inhibition significantly reduced the expression of several inflammatory and stress response genes following IL-1β activation, many of which were also decreased at the protein level (MCP-1, RANTES, G-CSF, MMP3, iNOS; n=4/group, p<0.05). Lastly, LC-MS/MS evaluation of lipid mediators in conditioned medium showed that TAK1 deletion increases production of several resolvins (RvE2, RvD1, RvD4) and lipoxins (LXA 4 , 15( R )-LXA 4 ) (n=3/group; p<0.05). Conclusion: TAK1 signaling in cardiac fibroblasts is a critical regulator of inflammation and immune cell recruitment post-MI. Fibroblast-specific TAK1 suppression improves cardiac function and structure in male mice, likely by attenuating inflammatory signaling and promoting pro-resolving lipid mediator production. Notably, the differences in outcomes observed between males and females may be attributed to previously documented sex-specific variations in inflammatory responses. NIH R01 HL168198, NIH F30 HL165813, This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.