Local dysregulation of the GPR17 receptor in neuroinflammatory diseases: implications for remyelination in multiple sclerosis

Introduction Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, in which inflammation and myelin disruption contribute to impaired electrical conduction. Oligodendrocyte precursor cells (OPCs) are massively recruited to the site of injury to myelinate damaged axons, but remyelination is often ineffective. For this reason, therapeutic strategies aimed at fostering this process could favourably influence disease development and the consequent disability. We have previously shown that the membrane receptor GPR17 timely regulates the early stages of OPC differentiation, but after reaching its highest levels in immature oligodendrocytes, it has to be down-regulated to allow terminal maturation. Any defect in its expression pattern leads to impairment in oligodendrocyte differentiation. Interestingly, overexpression of GPR17 was found in rodent models of cerebral trauma, ischemia and in lysolecithin induced focal demyelination. Instead, little is known about GPR17 changes in a demyelinating disease such as MS. On this basis, our aim was the characterization of GPR17 alterations in murine models of MS, namely experimental autoimmune encephalomyelitis (EAE) and cuprizone induced demyelination. Methods For EAE induction, either C57BL/6 wild-type or transgenic mice were immunized with the myelin oligodendrocyte glycoprotein (MOG) peptide and clinical scores were monitored daily. For the second model, mice were fed with 0.2% cuprizone supplemented diet for 5 weeks to induce de-myelination followed by switch to normal diet for 3 weeks to allow spontaneous re-myelination. Results In both models, we observed a marked and persistent upregulation of GPR17 in the OPCs accumulating at demyelinating lesions. However, transgenic GPR17iCreERT2-GFP reporter mice showed that only in the cuprizone model, reacting GFP+ cells contributed to re-myelination, whereas in EAE, GFP+ cells were blocked in an immature stage and never reached myelination stages, likely due to unfavourable inflammatory environment. Indeed, both infiltrating and resident cells can release inflammatory cytokines and contribute to both genic and epigenetic OPC reprogramming upon injury. Our recent data also suggested that GPR17 expression can be regulated by microRNAs, small non-coding RNAs, now emerging as master regulators of virtually all biological pathways. In particular, we demonstrated that miR-125a-3p impaired oligodendrocyte maturation at different levels and with different kinetics also by inhibiting GPR17. Furthermore, miR-125a-3p expression was altered in both MS models and in CSF of MS patients, suggesting a possible contribution of this miRNA to the pathogenesis of the disease. Conclusions These data suggest that the timely expression of GPR17 at the membrane of OPCs accumulating at demyelinating lesions is disrupted in MS models and could represent a new target to be modulated to support endogenous remyelination.