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

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.