Purinergic-cytokine signaling as a regulatory axis in neuroimmune development

Neurodevelopment is a biological process through which the nervous system grows, organizes, and matures. This process is guided by genetic programs and shaped by environmental influences. During neurodevelopment, microglia and astrocytes secrete neurotrophic factors and signaling molecules. These orchestrate neuroimmune interactions essential for healthy brain development. The activity of these cells is modulated by both intrinsic and environmental cues, including neuronal activity, synaptic communication, circulating small molecules and hormones, and peripheral immune cells that infiltrate the brain parenchyma. Within this framework, this review provides information on the physiological role of cytokines in driving key neurodevelopmental processes, along with evidence for purinergic coordination of cytokine signaling. Purinergic signaling operates through a limited repertoire of extracellular molecules, with outcomes determined by tightly regulated receptor expression and enzymatic degradation, which complicates precise fine-tuning. In contrast, cytokine signaling is largely defined by cytokine identity and receptor-specific downstream pathways, which enables greater specificity. The crosstalk between purines and cytokines is tightly regulated, forming a central signaling axis within neuroimmune communication. In this context, purinergic-cytokine signaling coordinates critical neurodevelopmental processes. These include progenitor proliferation, migratory trajectories, neurite growth, differentiation, and synaptic refinement.