Microglia Purinoceptor P2Y6: An Emerging Therapeutic Target in CNS Diseases

Abstract

The purinergic receptor P2Y6 is expressed in immune cells, including the microglia that are implicated in neurological disorders. Its ligand, UDP, is a signaling molecule that can serve as an "find-me" signal when released in significant quantities by damaged/dying cells. The binding of UDP by P2Y6R leads to the activation of different biochemical pathways, depending on the disease context and the pathological environment. Generally, P2Y6R stimulates phagocytosis. However, whether or not phagocytosis coincides with cell activation or the secretion of pro-inflammatory cytokines needs further investigation. The current review aims to discuss the various functions of P2Y6R in some CNS disorders. We present evidence that P2Y6R may have a detrimental or beneficial role in the nervous system, in the context of neurological pathologies, such as ischemic stroke, Alzheimer's disease, Parkinson's disease, radiation-induced brain injury, and neuropathic pain.

Keywords: P2Y6R; microglia; neuroinflammation; phagocytosis; pro-inflammatory cytokines.

Figure 1

Schematic of UDP/P2Y6R signaling, mediating microglial phagocytosis and chemotaxis. In the healthy CNS, homeostatic microglia (resting microglia) constantly survey and scan the cerebral microenvironment by continuously extending and retracting their ramified processes for the early recognition of damage-associated molecular patterns (DAMPs) such as ATP. Damaged CNS elements (neurons and oligodendrocytes) release or leak ATP/UTP. Furthermore, UTP is easily converted to UDP by ectonucleotidases. UDP acts as an “find-me” signal for P2Y6R. UDP/P2Y6R activates microglia, activated microglia move to the damaged area, and then subsequently recognize UDP as “find-us” signal, attached to the targets, and engulf them. As a result of microglia activation, they release a plethora of inflammatory and anti-inflammatory cytokines depending on the context of the disease. The types and levels of released cytokines differ from a disease to another. The context of a specific disease determines the harmful or the beneficial effects of microglia activation.