The natural β-glucan polysaccharide laminarin ameliorates microglial inflammation by metabolic reprogramming through...

Neuroinflammation, driven by the activation of immune cells such as microglia, is tightly linked to metabolic reprogramming, thereby emerging as a key therapeutic target. This study investigated the potential of laminarin, a natural β-glucan polysaccharide, to ameliorate immunometabolic dysfunction in lipopolysaccharide (LPS)-stimulated microglia. Laminarin potently suppressed the production of pro-inflammatory cytokines, reduced oxidative stress, and ameliorated metabolic dysfunction through the activation of sirtuin 1 (SIRT1), which was identified as a key molecular target. Molecular docking simulations predicted a high-affinity binding of its representative unit, laminarihexaose, to the SIRT1 allosteric activation site, leading to its effective activation. In LPS-challenged microglia, laminarin's ability to enhance cellular NAD⁺ levels via the NAD⁺ salvage pathway also contributed to SIRT1 activation. Furthermore, SIRT1 activation was linked to laminarin's capacity to promote the phosphorylation of AMP-activated protein kinase (AMPK), suggesting a potential positive feedback loop that reinforces the integrity of the SIRT1-AMPK axis. Laminarin prevented LPS-induced abnormal flux of the TCA cycle by regulating the related genes and the concentration of intermediates such as aconitic acid and 2-hydroxyglutaric acid. Laminarin's efficacy also extended to suppressing the compensatory glycolytic switch and ameliorating mitochondrial dysfunction by restoring the mitochondrial membrane potential and regulating genes involved in mitochondrial respiration. Collectively, these results suggest that laminarin ameliorates microglial inflammation and metabolic dysregulation by activating the SIRT1-AMPK axis to restore metabolic homeostasis. These findings position laminarin as a promising therapeutic candidate for neuroinflammatory disorders by targeting the crucial link between immunity and metabolism.