The P2Y-like receptor GPR17 as a sensor of damage and a new potential target in spinal cord injury

Traumatic spinal cord injury (SCI) is a devastating condition with an annual incidence of 15–40 cases per million and enormous social and health costs. Due to the compelling need for the discovery of new pharmacological targets whose modulation could effectively improve outcome after SCI, we focused on a new P2Y-like receptor, GPR17. It is activated by uracil nucleotides (e.g, UDP-glucose) and cysteinyl-leukotrienes (cysLTs), whose concentrations are markedly increased following injury, suggesting their possible role as “danger signals” to alert responses to tissue damage and start repair. In fact, we have demonstrated that blockade of GPR17 significantly prevented the progression of brain damage in a rodent model of focal brain ischemia, suggesting its contribution to neurodegeneration. In intact spinal cord, neurons, oligodendrocytes and ependymal cells lining the central canal express GPR17, which is never expressed by astrocytes. Following SCI, a marked death of GPR17+ neurons and oligodendrocytes inside the lesion was observed, followed by the appearance of proliferating GPR17+ microglia/macrophages migrating to and infiltrating into the lesion. Moreover, 72 hours after SCI, GPR17+ ependymal cells started to proliferate and to express GFAP (taken here as a marker of pluripotency), suggesting their reaction to injury and their “de-differentiation” to pluripotent progenitors. The in vivo knock-down of GPR17 by anti-sense oligonucleotides markedly reduced SCI-induced cell death and related histological and motor deficits. Taken together, our findings suggest that GPR17 may act as a “sensor” of damage, that is activated by nucleotides and cysLTs released in the lesioned area, and plays a crucial role in the early phases of tissue damage development. Moreover, its presence on pre-oligodendrocytes and precursor-like cells suggests GPR17 as a novel target for therapeutic manipulation to foster remyelination and functional repair in SCI.