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.