TRPM2 channel regulates cytokines production in astrocytes and aggravates brain disorder during lipopolysaccharide-induced endotoxin sepsis.

Sepsis is one of the most significant challenges in intensive care units, which is associated with increased morbidity and mortality. Sepsis-associated encephalopathy (SAE) is a severe complication which can cause death and serious disabilities. Calcium signaling in astrocyte is essential for cellular activation and the potential resolution of infection or inflammation in SAE patients. The transient receptor potential melastatin 2 (TRPM2) channel has been identified as a unique fusion of a Ca-permeable nonselective cation channel, which plays an important role in inflammation and immune response. Because of its role as an oxidative stress sensor in astrocytes, we investigated the function of TRPM2 in inflammation mediators (interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α) release, Bcl-2/E1B-19 K-interacting protein 3 (BNIP3), apoptosis inducing factor (AIF) and Endonuclease G (Endo G) expression. We showed that TRPM2-KO mice, when intraperitoneally (i.p) injected with LPS, exhibited better neurologic assessment scores and decreased inflammatory injury in hippocampal neurons compared with wild-type (WT) mice. The absence of TRPM2 triggered less production of inflammatory mediators (IL-1β, IL-6, TNF-α) and decreased apoptosis related proteins (BNIP3, AIF, Endo G) expressions in response to LPS induced sepsis. Furthermore, TRPM2-deficient astrocytes (transfected with TRPM2 siRNA) upon LPS stimulation also induced decreased IL-1β, IL-6 and TNF-α level. Our data suggested that decreased production of inflammatory cytokines and apoptosis related proteins with TRPM2 deletion could regulate inflammatory stress and decrease inflammatory injury in hippocampal neurons, and consequently, ameliorate brain disorder.