title: Activation of NOD2/RIPK2 pathway induces mitochondrial injury to oligodendrocyte precursor cells in vitro and CNS demyelination in vivo.
abstract: 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.
authors.affiliation: Department of Neurology, Multiple Sclerosis Research Center, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Natarajan
authors.forename: Song-Yi
authors.initials: SY
authors.lastname: Yao
authors.forename: Fanglin
authors.initials: F
authors.lastname: Zhang
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Sriram
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000166:cytology; D003337:Corpus Callosum / Q000187:drug effects / Q000378:metabolism; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology* / Q000628:therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010457:Peptidoglycan / Q000633:toxicity; D051381:Rats; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells; D013997:Time Factors
chemical_list: D007191:Indazoles; C512493:NOD2 protein, rat; D018696:Neuroprotective Agents; D053473:Nod2 Signaling Adaptor Protein; D010457:Peptidoglycan; D052248:Nitric Oxide Synthase Type I; D003576:Electron Transport Complex IV; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D042967:Electron Transport Complex I; C080122:7-nitroindazole
keywords: Mitochondria and demyelination; Nitric oxide synthase; Oligodendrocyte; Peptidoglycan