Glial-neuronal interactions via chemokine signaling in cerebral ischemia: Mechanisms and therapeutic implications

Cerebral ischemia (CI) triggers a cascade of cellular communication disruptions, with chemokines serving as key mediators of neuroinflammation and blood-brain barrier (BBB) dysfunction. This review outlines current knowledge on the specific functions of chemokines and their receptors in CI development, emphasizing their potential as therapeutic targets. It details the mechanisms of chemokine release, including the role of extracellular vesicles (EVs) from various glial and neuronal cells, and examines how post-translational modifications (PTMs) influence chemokine and receptor activity. The review also explores signaling pathways such as NF-κB, p38 MAPK, PI3K/AKT, and RhoA/ROCK, which are central to chemokine responses. A significant focus is on the bidirectional communication between neurons and glia, highlighting dynamic shifts in chemokine signaling from acute injury to chronic repair. By targeting this network—using receptor antagonists and modulating chemokine release—we aim to discover new therapeutic strategies. This comprehensive framework enhances understanding of the spatiotemporal and molecular intricacies of chemokine signaling in CI, guiding the development of precise interventions to support neuroprotection and functional recovery.