Molecular signaling pathways shaping astrocyte–microglia crosstalk in health and disease

While neuron-glia communication has been extensively investigated, the molecular dialogue between non-neuronal cells, particularly astrocytes and microglia, remains comparatively less explored. This bidirectional crosstalk plays a central role in maintaining central nervous system (CNS) homeostasis, coordinating responses to injury, and shaping neuroinflammatory dynamics. Astrocyte-microglia communication is mediated by a complex network of secreted factors and intracellular signaling pathways that shape glial activation states and functional outcomes. Among the best-characterized pathways, NF-κB, JAK/STAT3, MAPK/ERK, and Smad2/3 regulate the balance between pro-inflammatory and reparative responses and influence whether glial signaling promotes neurotoxicity or neuroprotection. In this mini-review, we summarize the molecular mechanisms underlying astrocyte-microglia crosstalk in physiological and pathological contexts, with particular emphasis on the secreted mediators that dynamically reprogram glial signaling networks. We also highlight how emerging experimental platforms, including human induced pluripotent stem cell-derived glia, brain organoids, and organ-on-chip systems, are helping to uncover human-specific and disease-relevant features of glial interaction. A better understanding of astrocyte-microglia molecular crosstalk may help define the signaling programs that sustain chronic neuroinflammation and neurodegeneration. Such insight could support the development of strategies aimed at restoring glial homeostasis and limiting disease progression.