Toll-like receptor 7 constrains efferocytosis in myocardial injury.

Toll-like receptor 7 (TLR7) is an endosomal sensor of single-stranded RNA that is highly expressed in macrophages and contributes to post-infarct inflammation. Whether TLR7 also restrains macrophage reparative function, particularly efferocytosis and clearance of inflammatory debris, remain unclear. Using a murine model of myocardial ischemia-reperfusion (I/R) injury, we showed that TLR7 deficiency mitigated inflammation, reduced infarct size and alleviated adverse ventricular remodeling. Beyond its anti-inflammatory effects, TLR7 deficiency reprogrammed macrophages toward a reparative phenotype, characterized by decreased pro-inflammatory cytokine production and increased expression of anti-inflammatory mediators, including IL-10 and TGF-β, consistent with M2-like polarization. Single-cell RNA sequencing revealed a subset-specific mechanism in which TLR7 deficiency suppressed inflammatory signaling in M1 macrophages while enhancing efferocytosis-related pathways in M2 macrophages. This was accompanied by upregulation of key phagocytic receptors and machinery, including CD36, LRP1, MerTK, AXL and Rac1, and functionally translated into enhanced efferocytic capacity and reduced apoptotic burden. Notably, TLR7 deficiency also promoted macrophage-mediated clearance of neutrophil extracellular traps (NETs) without affecting NETosis, identifying a previously unrecognized role for TLR7 in regulating NET resolution. Consistent with these findings, NET formation was observed following myocardial injury in both murine I/R models and patients undergoing percutaneous coronary intervention.In conclusion, our data identify TLR7 as a macrophage-intrinsic checkpoint that limits efferocytosis and NET disposal, thereby impairing inflammation resolution after myocardial injury. Targeting TLR7 may therefore represent a therapeutic strategy to suppress excessive inflammation while restoring pro-resolving macrophage functions and improving cardiac repair.