Human umbilical cord mesenchymal stem cell‐derived exosomes attenuate neuroinflammation and oxidative stress through the NRF2 / NF‐κB / NLRP3 pathway

Abstract Aims We investigated whether human umbilical cord mesenchymal stem cell (hUC‐MSC)‐derived exosomes bear therapeutic potential against lipopolysaccharide (LPS)‐induced neuroinflammation. Methods Exosomes were isolated from hUC‐MSC supernatant by ultra‐high‐speed centrifugation and characterized by transmission electron microscopy and western blotting. Inflammatory responses were induced by LPS in BV‐2 cells, primary microglial cultures, and C57BL/6J mice. H 2 O 2 was also used to induce inflammation and oxidative stress in BV‐2 cells. The effects of hUC‐MSC‐derived exosomes on inflammatory cytokine expression, oxidative stress, and microglia polarization were studied by immunofluorescence and western blotting. Results Treatment with hUC‐MSC‐derived exosomes significantly decreased the LPS‐ or H 2 O 2 ‐induced oxidative stress and expression of pro‐inflammatory cytokines (IL‐6 and TNF‐α) in vitro, while promoting an anti‐inflammatory (classical M2) phenotype in an LPS‐treated mouse model. Mechanistically, the exosomes increased the NRF2 levels and inhibited the LPS‐induced NF‐κB p65 phosphorylation and NLRP3 inflammasome activation. In contrast, the reactive oxygen species scavenger NAC and NF‐κB inhibitor BAY 11–7082 also inhibited the LPS‐induced NLRP3 inflammasome activation and switched to the classical M2 phenotype. Treatment with the NRF2 inhibitor ML385 abolished the anti‐inflammatory and anti‐oxidative effects of the exosomes. Conclusion hUC‐MSC‐derived exosomes ameliorated LPS/H 2 O 2 ‐induced neuroinflammation and oxidative stress by inhibiting the microglial NRF2/NF‐κB/NLRP3 signaling pathway.