IL-10 Drives Macrophage to Myofibroblast Transition Promoting Chronic Fibrosis in the Failing Heart 9287

Abstract Description Chronic fibrosis underlies many chronic diseases, compromising organ function and contributing to high mortality, particularly in heart failure. Although macrophages (M?) were regarded as passive propagators of fibrotic remodeling through inflammation, recent findings revealed an alternative mechanism of M?-to-myofibroblast transition (MMT), which accounts for up to 50% of myofibroblasts in murine and human chronic disease models, highlighting a new target for intervention in chronic fibrotic pathologies. Using a classic high blood pressure mouse model, our lab has identified a significant prevalence (>50%) of MMT (CD68+/α-SMA+) in the hearts of hypertensive mice compared to control mice (<10%). This MMT was met with astounding cardiac fibrotic remodeling and degraded heart function; however, the precise cell signals required for MMT and its potential exacerbation of fibrosis in heart failure remain unknown. Notably, we have identified interleukin-10 (IL10) as a key driver of this pathological M? phenotype and demonstrated a synergistic effect between IL10 and elevated blood pressure in promoting MMT. These findings underscore a critical role for IL10 signaling-mediated MMT in the chronic fibrotic pathology of heart failure. Ongoing and future work will leverage IL10-reporter mice (Vert-X) and monocyte-specific knockout of IL10-receptor (IL10R) mice to determine the pathogenic source of IL10 overproduction and regulation of IL10R expression under high mechanical pressure. Funding Sources NIH RO1-HL146713 AHA 23TPA1076467 NIH R25-GM083247 Topic Categories Cytokines and Chemokines and Their Receptors (CCR)