Transient receptor potential melastatin 2 protects mice against polymicrobial sepsis by enhancing bacterial clearance (INC6P.342)

Abstract

Abstract Background: Recent studies suggest that transient receptor potential melastatin 2 (TRPM2) channel plays an important role in inflammation and immune response. However, the role and mechanism of TRPM2 in polymicrobial sepsis remains unclear. Methods: We explored the effects of genetic disruption of TRPM2 on mortality, bacterial clearance, organ injury, and systemic inflammation during cecal ligation and puncture (CLP)-induced sepsis. Electrophysiology, immunoblot, bacterial clearance experiment, and quantitative real-time polymerase chain reaction were used to explore the role and mechanism of TRPM2 in sepsis. Results: After CLP, Trpm2-KO mice had increased mortality compared with WT mice. The increased mortality was associated with increased bacterial burden, organ injury, and systemic inflammation. Disruption of TRPM2 decreased HO-1 expression and increased bacterial burden in bone marrow-derived macrophages (BMDMs). Pretreatment of Trpm2-KO mice with HO-1 inducer reversed the susceptibility of Trpm2-KO mice to sepsis by enhancing bacterial clearance. In addition, septic patients with lower monocytic TRPM2 and HO-1 mRNA levels had a worse outcome compared with septic patients with normal monocytic TRPM2 and HO-1 mRNA levels. TRPM2 levels correlated with HO-1 levels in septic patients. Conclusions: Our data demonstrate a protective role of TRPM2 in controlling bacterial clearance during polymicrobial sepsis, possibly by regulating HO-1 expression.