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

  • CNS Neurosci Ther. 2023 Sep 12. doi: 10.1111/cns.14454.
Ji Che  1  2 ,  Hui Wang  1  2 ,  Jing Dong  1  2 ,  Yuanyuan Wu  1  2 ,  Haichao Zhang  3 ,  Lei Fu  3 ,  Jun Zhang  1  2
Affiliations
  • 1. Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3. Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, China.
PMID: 37697971 DOI: 10.1111/cns.14454
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. H2 O2 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 H2 O2 -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/H2 O2 -induced neuroinflammation and oxidative stress by inhibiting the microglial NRF2/NF-κB/NLRP3 signaling pathway.

Keywords
NLRP3; human umbilical cord mesenchymal stem cell (hUC-MSC)-derived exosomes; microglia; neuroinflammation; oxidative stress.
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