Chitosan Oligosaccharide Attenuates Neuroinflammation by Regulating Microglial Immunometabolic Reprogramming via the mTOR Signaling Pathway

Microglia, the primary immune cells in the central nervous system (CNS), undergo immunometabolic reprogramming under neuroinflammatory conditions. Chitosan oligosaccharide (COS) exhibits multiple biological activities, including anti-inflammatory and antioxidant effects, yet its influence on microglial metabolism remains unclear. Here, we demonstrate that lipopolysaccharide (LPS) triggers immunometabolic alterations in microglia via the mechanistic target of the rapamycin (mTOR) pathway. COS effectively normalized immunometabolism by modulating mTOR signaling, enhancing Oxidative Phosphorylation (OXPHOS), attenuating anaerobic glycolysis and pentose phosphate pathway (PPP) activation, promoting M2 polarization, and increasing adenosine triphosphate (ATP) production. In vivo, COS suppressed mTOR activation in the hippocampal and cortical regions, improved cognitive and spatial memory, and reduced neuronal damage in LPS-challenged mice. These findings suggest that COS modulates microglial immunometabolic reprogramming through mTOR signaling, thereby augmenting immune homeostasis and cognitive performance. In conclusion, our findings propose COS as a promising therapeutic candidate for the prevention and treatment of neuroinflammation-related disorders.

M2 polarization; chitosan oligosaccharide (COS); immunometabolic reprogramming; mTOR signaling pathway; microglia; neuroinflammation; oxidative phosphorylation (OXPHOS).