Paper Title

Abstract - Microglia is a significant immune defense regulator of the central nervous system. The overactivation of microglia due to local and systemicinfectionleads to the excessive production of inflammatory mediators. Thus, resulting in neurodegeneration and psychiatric disorders. The repetitive exposure of microglia to endotoxin, such aslipopolysaccharide (LPS),has been reported to offer neuroprotective effects due to a phenomenon termed endotoxin tolerance. However, the regulatory mechanisms underlying the association between microglia activation and systemic inflammation and the adaptive response of microglia cells in endotoxin tolerance effect are far to be elucidated. In this study, we intraperitoneally injected mice with low-dose LPS (0.5mg/kg) for 4 consecutive days to induce endotoxin tolerance. Then, neuroinflammation was stimulated by administering high-dose LPS (5 mg/kg) through intraperitoneal injection for 6 or 24 hours. We found that preconditioning with low-dose LPS reversed the LPS-induced social avoidance by reducing microglia activation and lowering the recruitment of proinflammatory cytokine-producing peripheral leukocytes to the brain.Moreover, LPS-stimulated inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, suppressor of cytokine signaling (SOCS)3, tumor necrosis factor- (TNF-), and C-X-C motif ligand 1 (CXCL1) in hippocampus and stratum were decreased in LPS-tolerized mice. These findings indicated that endotoxin tolerance of innate immune cells can be induced by a continuouspre-exposure to a low-dose LPS. Besides, LPS preconditioning regulated pro-inflammatory mediators, including SOCS3, COX-2, PGE2, iNOS, nitric oxide (NO), TNF-, interleukin (IL)-6, and IL-1 induced by LPS stimulation in microglial cells. Taken together, this study provides therapeutic strategies that will be beneficial forthe management of inflammation-associated disorders. Keywords - Endotoxin Tolerance; Neuroinflammation; Microglial Cells; Behavior Dysfunction; Proinflammatory Cytokines