Dysfunctional Crosstalk in Ischemic Stroke: Exploring Network Failure and Emerging Communication Pathways

Ischemic stroke damages complex, interconnected communication networks in addition to causing the destructive collapse of cells. All elements of the neurovascular unit (NVU), including the often disregarded glycocalyx and invading peripheral immune cells, interact dynamically and frequently contradict one another in their pathophysiological processes, which extend beyond neurons. This paper reviews developments in intercellular communication pathways that regulate brain injury and repair after cerebral ischemia. The intricate signaling networks among neurons, astrocytes, microglia, oligodendrocytes, endothelial cells, pericytes, and lymphocytes were comprehensively analyzed. This review goes beyond conventional viewpoints to highlight major findings, ongoing debates, and critical research gaps associated with each interaction. This study investigated the dual nature of glial responses by analyzing diverse activation states of glial cells, the mechanisms underlying blood-brain barrier (BBB) disruption, including glycocalyx degradation, and the complex immunoregulatory roles of lymphocyte subsets, such as regulatory T cells (Tregs), regulatory B cells (Bregs), and γδ T cells. In addition to classical soluble factor signaling, emerging communication mechanisms, including extracellular vesicles (EVs), tunneling nanotubes (TNTs), and migrasomes, were investigated, and these mechanisms may be involved in ischemic pathophysiology. Contradictory data and mechanistic evidence were assessed for every communication pathway; knowledge gaps were identified, and specific experiments were proposed to resolve these uncertainties. Finally, these observations were integrated into a discussion of advanced therapeutic approaches based on network modulation. This review offers a potential framework for discovering new system-based treatment targets targeted at rewiring harmful crosstalk and fostering strong neurological recovery by characterizing ischemic stroke as a progressive failure of intercellular communication.