Klf9 promotes the repair of myocardial infarction by regulating macrophage recruitment and polarization

The inflammatory response after myocardial infarction (MI) is a precisely regulated process that greatly affects subsequent wound healing and remodeling. However, the understood about the process are still limited. Macrophages are critically involved in inflammation resolution after MI. Krüppel-like factor 9 (Klf9) is a C2H2 zinc finger-containing transcription factor that has been implicated in glucocorticoid regulation of macrophages. However, the contribution of Klf9 to macrophage phenotype and function in the context of MI remains unclear. Our study revealed that KLF9 deficiency results in higher mortality and cardiac rupture rate, as well as a considerable exacerbation in cardiac function. Single-cell RNA sequencing and flow cytometry analyses reveals that, compared to WT mice, Klf9-/- mice display excessive neutrophil infiltration, insufficient macrophage infiltration, and a reduced proportion of Monocyte-derived CD206+ macrophages post-MI. Moreover, the expression of IFN-γ-STAT1 pathway genes in Klf9-/- cardiac macrophages is dysregulated, characterized by insufficient expression at 1 day post-MI and excessive expression at day 3 post-MI. Mechanistically, Klf9 directly binds to the promoters of Stat1 gene, regulating its transcription. Overall, these findings indicates that Klf9 beneficially influences wound healing after MI through modulating macrophage recruitment and differentiation by regulating the IFN-γ-STAT1 signal pathway.