Abstract
Microglia have been proposed to play a pivotal role in the inflammation response of the CNS by expressing a range of proinflammatory enzymes and cytokines under pathological stimulus. Our previous study has confirmed that Nogo receptor (NgR), an axon outgrowth inhibition receptor, is also expressed on microglia and regulates cell adhesion and migration behavior in vitro. In the present study, we further investigated the proinflammatory effects and possible mechanisms of Nogo on microglia in vitro. In this study, Nogo peptide, Nogo-P4, a 25-amino acid core inhibitory peptide sequence of Nogo-66, was used. We found that Nogo-P4 was able to induce the expression of inducible nitric-oxide synthase and cyclooxygenase-2 and the release of proinflammatory cytokines, including IL-1β, TNF-α, NO, and prostaglandin E2 in microglia, which could be reversed by NEP1-40 (Nogo-66(1-40) antagonist peptide), phosphatidylinositol-specificphospholipase C, or NgR siRNA treatment. After Nogo-P4 stimulated microglia, the phosphorylation levels of NF-κB and STAT3 were increased obviously, which further mediated microglia expressing proinflammatory factors induced by Nogo-P4. Taken together, we concluded that Nogo peptide could directly take part in CNS inflammatory process by influencing the expression of proinflammatory factors in microglia, which were related to the NF-κB and STAT3 signal pathways. Besides neurite outgrowth restriction, the Nogo/NgR signal might be involved in multiple processes in various inflammation-associated CNS diseases.
Highlights
Nogo receptor (NgR) is expressed on microglia and regulates cell adhesion and migration behavior
Stimulation with Nogo-P4 Increased Microglia Expressing iNOS and COX-2 as Well as Releasing IL-1, TNF-␣, NO, and PGE2—To investigate the effects of Nogo-P4 on the production of proinflammatory enzymes and cytokines in microglia, wells were precoated with Nogo-P4 (100 g/ml) or Rtn-P4 (100 g/ml), and primary cultured microglia were added into the wells and cultured for 6, 12, or 24 h
Our results indicated that Nogo peptide elevated the production of proinflammatory cytokines of microglia in vitro, which was mediated by NF-B and STAT3 signal pathways
Summary
Results: Nogo/NgR signal induced the expression of proinflammatory factors in microglia through NF-B and STAT3 signal pathways. Conclusion: Nogo peptide could directly take part in CNS inflammatory process by influencing the expression of proinflammatory factors in microglia. Significance: Nogo/NgR signal might be involved in multiple processes in various inflammation-associated CNS diseases. Our previous study has confirmed that Nogo receptor (NgR), an axon outgrowth inhibition receptor, is expressed on microglia and regulates cell adhesion and migration behavior in vitro. We concluded that Nogo peptide could directly take part in CNS inflammatory process by influencing the expression of proinflammatory factors in microglia, which were related to the NF-B and STAT3 signal pathways. The Nogo/NgR signal might be involved in multiple processes in various inflammation-associated CNS diseases
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