Atorvastatin Regulates the Efferocytosis of Macrophages to Promote Hematoma Absorption and Inflammation Resolution in Experimental Subdural Hematoma

Macrophage-mediated efferocytosis is crucial for hematoma absorption and inflammation resolution in intracranial hemorrhages. We previously demonstrated that atorvastatin (ATO) expedites the absorption of subdural hematoma (SDH); however, the extent to which this therapeutic effect is associated with ATO-mediated modulation of macrophage efferocytosis remains unclear. In this study, we established a rat model of SDH through autologous blood transfusion into the subdural space. We used primary bone marrow-derived macrophages (BMDMs) to investigate the roles of heme and ATO. The results of enzyme-linked immunosorbent assay and flow cytometry demonstrated that, in addition to its proinflammatory effect, heme also inhibits macrophage efferocytosis. However, ATO reversed this inhibition of efferocytosis in both in vivo and in vitro experiments. Transcriptomic analysis of BMDMs revealed that ATO promotes Krüppel-like factor 4 (KLF4) expression and is mainly enriched in phagocytosis and lysosome-related pathways. Finally, ATO restored the heme-induced reduction in the macrophage phagocytic rate and impairment of lysosomal function. However, KLF4 knockout abolished the beneficial effects of ATO. In conclusion, this study demonstrated that ATO ameliorates heme-inhibited efferocytosis via KLF4, thereby promoting hematoma absorption. We demonstrated a novel mechanism of ATO in the treatment of SDH, providing a new therapeutic prospect for patients (IRB2022-YX-007-01).