TREM2-Mediated Microglial Pyroptosis: Unveiling the Neuroprotective Role of Diosmetin in Spinal Cord Ischemia-Reperfusion Injury

Abstract

Background Spinal cord ischemia-reperfusion injury (SCII) is a severe neurological condition marked by neuronal damage and functional impairments. The contribution of microglial pyroptosis, an inflammatory form of cell death, to SCII's development is increasingly acknowledged. Yet, the complex molecular mechanisms and potential therapeutic strategies targeting microglial pyroptosis in SCII are not fully understood. Methods Our research utilized both in vivo and in vitro models to evaluate the influence of TREM2 modulation on microglial pyroptosis and neuronal function in SCII. Principal methods included Tarlov scoring, Western blot analysis, Chromatin Immunoprecipitation (CHIP) and histological techniques, with an emphasis on proteins such as Forkhead Box O1 (FOXO1) and pyroptosis-related proteins to decipher the underlying mechanisms. Molecular docking was employed to investigate the interaction between the small molecule diosmetin and TREM2. Results We observed a marked increase in TREM2 expression following SCII, and demonstrated that TREM2 overexpression mitigated microglial pyroptosis and enhanced motor neuron functionality. Further investigation revealed that TREM2 engagement leads to the activation of Forkhead Box O1 (FOXO1) phosphorylation through the Phosphatidylinositol 3-Kinase (PI3K)/Protein Kinase B (AKT) signaling pathway. This activation sequence culminates in the downregulation of Gasdermin D (GSDMD), the primary effector of pyroptosis. Additionally, we identified diosmetin, a natural compound known for its anti-inflammatory and antioxidant effects, as a potent modulator of TREM2-mediated microglial pyroptosis. Experimental data demonstrate diosmetin's binding affinity to TREM2, conferring neuroprotection by impeding microglial pyroptosis through the TREM2/PI3K/AKT/FOXO1/GSDMD axis. Conclusion Our findings underscore the pivotal role of TREM2 in microglial pyroptosis and its therapeutic potential in SCII, positioning diosmetin as a viable pharmacological candidate for SCII prevention and therapy.