Tet2 Maintains Genome Stablity In Cardiac Myeloid Cells

Myeloid cells play critical roles in the regulation of myocardial injury and repair. Clonal hematopoiesis (CH)-related mutations in genes, such as Ten-eleven Translocation 2 (TET2), can impair myeloid cells and are associated with increased risk of cardiovascular disease. To identify the subsets of myeloid cells that are impacted by Tet2 loss-of-function (LOF) and illuminate how Tet2 LOF disrupts normal myocardial repair, we analyzed the dynamics of myeloid cells in a myeloid-specific Tet2-deficient mouse model after ischemia-induced myocardial infarction (MI). We observed a substantial increase of neutrophils in the post-MI mice, which contributes to adverse outcomes during heart repair. Mechanistically, Tet2-deficient myeloid cells exhibited increased genome instability, accompanied with augmented activation of the intracellular innate immune response. Furthermore, pharmacological inhibiting intracellular innate immunity resulted in significantly reduced neutrophils in Tet2-deficient mice after MI and reversal of deleterious cardiac outcomes. Findings from this study are consistent with the conclusion that targeting the innate immune pathways is a viable therapeutic option to reduce the risk of cardiovascular diseases in CH individuals bearing TET2 LOF mutations.