Myelin activates FAK/Akt/NF-κB pathways and provokes CR3-dependent inflammatory response in murine system

Xin Sun, Xi Wang, Tianxiang Chen, Tianyi Li, Kai Cao, Andrew Lu, Yongxiong Chen, Dongming Sun, Jianhong Luo, Jianqing Fan, Wise Young, Yi Ren

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57 Scopus citations

Abstract

Inflammatory response following central nervous system (CNS) injury contributes to progressive neuropathology and reduction in functional recovery. Axons are sensitive to mechanical injury and toxic inflammatory mediators, which may lead to demyelination. Although it is well documented that degenerated myelin triggers undesirable inflammatory responses in autoimmune diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), there has been very little study of the direct inflammatory consequences of damaged myelin in spinal cord injury (SCI), i.e., there is no direct evidence to show that myelin debris from injured spinal cord can trigger undesirable inflammation in vitro and in vivo. Our data showed that myelin can initiate inflammatory responses in vivo, which is complement receptor 3 (CR3)-dependent via stimulating macrophages to express pro-inflammatory molecules and downregulates expression of anti-inflammatory cytokines. Mechanism study revealed that myelin-increased cytokine expression is through activation of FAK/PI3K/Akt/NF-κB signaling pathways and CR3 contributes to myelin-induced PI3K/Akt/NF-κB activation and cytokine production. The myelin induced inflammatory response is myelin specific as sphingomyelin (the major lipid of myelin) and myelin basic protein (MBP, one of the major proteins of myelin) are not able to activate NF-κB signaling pathway. In conclusion, our results demonstrate a crucial role of myelin as an endogenous inflammatory stimulus that induces pro-inflammatory responses and suggest that blocking myelin-CR3 interaction and enhancing myelin debris clearance may be effective interventions for treating SCI.

Original languageEnglish (US)
Article numbere9380
JournalPloS one
Volume5
Issue number2
DOIs
StatePublished - Feb 23 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Sun, X., Wang, X., Chen, T., Li, T., Cao, K., Lu, A., Chen, Y., Sun, D., Luo, J., Fan, J., Young, W., & Ren, Y. (2010). Myelin activates FAK/Akt/NF-κB pathways and provokes CR3-dependent inflammatory response in murine system. PloS one, 5(2), [e9380]. https://doi.org/10.1371/journal.pone.0009380