Activation of NOD2/RIPK2 pathway induces mitochondrial injury to oligodendrocyte precursor cells in vitro and CNS demyelination in vivo.

Natarajan C, Yao SY, Zhang F, Sriram S
J Neuroimmunol. 2013 265 (1-2): 51-60

PMID: 24169446 · DOI:10.1016/j.jneuroim.2013.09.009

We examined the activation of innate immune pathway mediated by nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in oligodendrocyte precursor cells (OPCs). We show that activation of NOD2 by ligand peptidoglycan (PGN) leads to the recruitment and phosphorylation of receptor-interacting serine/threonine kinase 2 (RIPK2). Phosphorylation of RIPK2 is followed by phosphorylation of neuronal nitric oxide synthase (nNOS), increase in NOS activity and subsequent accumulation of nitric oxide (NO) mediated N-tyrosinylated compounds in OPCs. The reversal of NOS activity by the nNOS inhibitor 7-nitroindazole (7-NI), but not by the iNOS inhibitor L-canavanine, supported the conclusion that the increased NOS activity was due to the selective activation of nNOS in OPCs. In addition, NO mediated injury to OPC was reflected in reduction in activity of respiratory enzymes such as complex I and IV, decrease in mitochondrial membrane potential and release of cytochrome-C from mitochondria. Furthermore, intracerebral injection of PGN into corpus callosum (CC) of rats led to the development of demyelination, which appeared as early as by day 3 post-injection, and involved the trunk of the CC by day 14. Accumulation of N-tyrosinylated proteins was seen in oligodendrocytes in regions of the CC which were in close proximity to the injection site. Taken together, these results suggest that PGN induced formation of NO, mitochondrial dysfunction and accumulation of N-tyrosinylated proteins in oligodendrocytes are likely mediators of central nervous system demyelination.

© 2013. Published by Elsevier B.V. All rights reserved.

MeSH Terms (22)

Animals Animals, Newborn Cerebral Cortex Corpus Callosum Demyelinating Diseases Disease Models, Animal Dose-Response Relationship, Drug Electron Transport Complex I Electron Transport Complex IV Gene Expression Regulation Indazoles Mitochondria Neuroprotective Agents Nitric Oxide Synthase Type I Nod2 Signaling Adaptor Protein Oligodendroglia Peptidoglycan Rats Receptor-Interacting Protein Serine-Threonine Kinase 2 Signal Transduction Stem Cells Time Factors

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