From danger to resolution: targeting purinergic signaling in CNS diseases

The central nervous system (CNS) is a dynamic immunological environment, where specialized interfaces, immune reservoirs, and metabolic clearance pathways, such as the glymphatic system, orchestrate immune surveillance and homeostasis. Within this intricate network, purinergic signaling, mediated by nucleotides like ATP and adenosine, emerges as a critical regulator of immune responses, inflammation resolution, and tissue repair. Adenosine, drives immunosuppression and immune exhaustion, shaping the balance between neuroprotection and neurodegeneration. Purinergic signaling influences a diverse array of cells, including platelets, neutrophils, dendritic cells, lymphocytes, macrophages/microglia, astrocytes, oligodendrocytes as well as neurons, each contributing uniquely to CNS immune dynamics. Dysregulation of this signaling network is implicated in major neurodegenerative and neurological diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, and traumatic brain injury (TBI). Recent advances in therapeutic strategies targeting purinergic receptors, such as A_2AR and P2X₇, have demonstrated promising clinical potential, offering new avenues for immunomodulation and neuroprotection. This review synthesizes current understanding of purinergic signaling in CNS immunity, explores its role in disease pathogenesis, and discusses innovative therapeutic approaches. By framing purinergic signaling as a tunable "rheostat", we highlight its potential to shift the CNS from danger to resolution, paving the way for precision immunotherapies in neurological disorders.