TAK1 Signaling in Cardiac Fibroblast Contributes to Inflammation Resolution Post Myocardial Infarction

Introduction: Resident cardiac fibroblasts are often defined by their extraordinary capacity to deposit extracellular matrix after cardiac injury; however, fibroblasts also react avidly to pro-inflammatory stimuli, suggesting that they may also be mediators of inflammation. Initially identified as a TGFβ responsive enzyme, TGF-β activated kinase 1 (TAK1) has been shown to be significant in regulating pro-inflammatory signaling in several disease models. The goal of this study was to understand how fibroblasts integrate pro-inflammatory signals to regulate acute inflammation following myocardial infarction (MI). We hypothesize that cardiac fibroblasts utilize a TAK1-dependent mechanism to integrate pro-inflammatory signals and orchestrate the cellular immune response following injury. Methods and Results: To create a fibroblast-specific model for TAK1 knockdown, TAK1 fl/fl mice were bred to Col1a2-CreERT mice. Following 2 weeks of tamoxifen chow feeding, both Cre− and Cre+ TAK1 fl/fl mice underwent permanent coronary ligation to induce MI. Three days following MI, immune cell populations from the heart, spleen, and peripheral blood were evaluated through flow cytometry. Deletion of TAK1 in fibroblasts in vivo diminished neutrophils and Ly6C low patrolling monocytes populations in the heart and decreased the number of CCR2neg resident macrophages after MI (n=10/group; p<0.05). Interestingly, circulating levels of neutrophils in the peripheral blood as well as those in the spleen were not significantly different between the groups. To determine how TAK1 may regulate pro-inflammatory signaling, isolated cardiac fibroblasts from TAK1 fl/fl mice were treated with Ad-CMV-iCre and were subsequently treated with IL1β. Notably, TAK1 knockdown suppressed IL1β-dependent p-JNK and NFκB signaling as well as MMP3 production. Further LC-MS/MS evaluation of lipid mediators in conditioned medium showed that deletion of TAK1 significantly increased fibroblast-derived resolvins (RvE2, RvD1, RvD4, RvE4) and lipoxins (LXA4, 15( R)-LXA4) (n= 3-5; p<0.05). Conclusion: Resident cardiac fibroblasts regulate the acute immune response following MI via a TAK1-dependent mechanism. Secreted factors derived from cardiac fibroblasts likely play a pivotal role in shaping the inflammatory and immune response after MI. NIH and AHA. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.