The Nogo/Nogo Receptor (NgR) Signal Is Involved in Neuroinflammation through the Regulation of Microglial Inflammatory Activation

• Published in: The Journal of biological chemistry Vol. 290; no. 48; pp. 28901 - 28914
• Main Authors: Fang, Yinquan, Yan, Jun, Li, Chenhui, Zhou, Xiao, Yao, Lemeng, Pang, Tao, Yan, Ming, Zhang, Luyong, Mao, Lei, Liao, Hong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.11.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Line; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Dinoprostone - genetics; Dinoprostone - metabolism; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Mice; microglia; Microglia - metabolism; Microglia - pathology; Myelin Proteins - genetics; Myelin Proteins - metabolism; Neurobiology; neurodegenerative disease; neuroinflammation; NF-kappa B - genetics; NF-kappa B - metabolism; NF-kappaB; NgR; Nitric Oxide - genetics; Nitric Oxide - metabolism; Nogo peptide; Nogo Proteins; Nogo Receptor 1; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Signal Transduction; STAT3; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; neurodegenerative disease; neuroinflammation; Nogo peptide; STAT3; NgR; NF-kappaB; microglia
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.678326

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. Background: NgR is expressed on microglia and regulates cell adhesion and migration behavior. Results: Nogo/NgR signal induced the expression of proinflammatory factors in microglia through NF-κB 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.