TREM‐1 Promotes Microglial Pyroptosis and Mitochondrial Fission in Intracerebral Hemorrhage via the PI3K/AKT Pathway

TREM-1, a pro-inflammatory factor, aggravates neuroinflammation following intracerebral hemorrhage (ICH). Both pyroptosis and mitochondrial dysfunction play a vital role in the further injury of ICH. However, whether TREM-1 regulates microglial pyroptosis and mitochondrial fission, and the potential mechanisms underlying these processes, remains unclear. A mouse model of ICH was established via stereotactic injection of collagenase VII-S. To knock down TREM-1 in vivo, AAV9-Iba1-TREM-1 was injected into the right basal ganglia. Additionally, the TREM-1-specific inhibitor LP17 was administered intranasally. Neurological function was assessed using behavioral assessments. In vitro, BV2 was stimulated with hemin to mimic ICH. LP17, NLRP3 inhibitor MCC950, TREM-1 agonist antibody Mab1187, and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 were used to investigate the mechanisms underlying TREM-1-mediated microglial pyroptosis and mitochondrial fission. Immunofluorescence staining, Western blot, RT-qPCR, and transmission electron microscopy were employed to evaluate microglial pyroptosis and mitochondrial fission. Both pharmacological inhibition and AAV-mediated knockdown of TREM-1 significantly improved neurological function, attenuated microglial pyroptosis and mitochondrial fission in ICH mice. TREM-1 was shown to drive microglial pyroptosis through the NLRP3 inflammasome. Furthermore, the PI3K/AKT signaling pathway was demonstrated to regulate TREM-1-induced microglial pyroptosis and mitochondrial fission. This study provides the first evidence that TREM-1 promotes microglial pyroptosis and mitochondrial fission following ICH via the PI3K/AKT signaling pathway. These findings highlight TREM-1 as a potential therapeutic target for mitigating neuroinflammation and neuronal damage in ICH.