ApoE impairs microglial efferocytosis by targeting Gas6/ MerTK in a mouse model of acute seizure

Epilepsy, a neurological condition, is characterized by frequent, spontaneous seizures. Both apolipoprotein E (ApoE) and TAM (Tyro3, Axl and MerTK) receptors, the key efferocytosis receptors, have been associated with the pathological mechanisms underlying epilepsy. Nevertheless, little is known about how they interact or the molecular mechanisms. Here, we explored how ApoE and microglial efferocytosis interact in a mouse model of acute seizures caused by kainic acid (KA). KA exposure reduced microglial efferocytosis that is dependent on growth arrest-specific protein 6 (Gas6)/MER proto-oncogene tyrosine kinase (MerTK). Additionally, KA treatment increased microglial ApoE expression, whereas ApoE knockout restored Gas6/MerTK-mediated microglial efferocytosis and alleviated KA-induced seizures and neuronal injury. Furthermore, KA exposure promoted ApoE immunoprecipitation with nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3). ApoE knockout suppressed KA-induced NLRP3 inflammasome activation. Interestingly, KA-induced seizures and neuronal injury were lessened by hippocampal NLRP3 knockdown, which further preserved Gas6/MerTK-dependent microglial efferocytosis. Furthermore, exogenous delivery of recombinant Gas6 had anti-seizure and neuroprotective benefits in addition to restoring microglial efferocytosis function. Collectively, ApoE stimulates NLRP3 inflammasome activation and targets Gas6/MerTK in seizure prone mice, thereby impairing microglial efferocytosis. For the treatment of seizures, the ApoE-NLRP3-Gas6/MerTK axis may represent a potential therapeutic target.