Chemokine Networks in Blood-Brain Barrier Regulation: Bidirectional Mechanisms, Clinical Translation, and Precision...

The blood-brain barrier (BBB), a core component of the neurovascular unit (NVU), meticulously regulates material exchange between the blood and brain parenchyma, serving as a critical barrier for maintaining the homeostasis of the central nervous system (CNS). Neuroinflammation, a pivotal response of the CNS to injury and disease, can disrupt NVU homeostasis when excessive or persistent, acting as a core pathogenic driver of various intractable neurological disorders. Chemokines, as key signaling molecules guiding the directional migration of immune cells, form the central hub mediating the dynamic regulation of neuroinflammation and the BBB. However, existing studies mostly focus on single disease systems or chemokine families, neglecting the bidirectional heterogeneity of different chemokine axes in BBB regulation and the common regulatory rules across diseases, while lacking systematic exploration of clinical translation challenges caused by the redundancy and spatiotemporal heterogeneity of the chemokine network. This review systematically clarifies the bidirectional regulatory effects of the core axes of the three major chemokine families (e.g., CCL2/CCR2, CXCL12/CXCR4, CX3CL1/CX3CR1) on the BBB. For the first time, we integrate a multi-dimensional regulatory model based on concentration, location, and time to analyze their molecular mechanisms and regulatory heterogeneity in promoting BBB disruption under pathological conditions versus mediating barrier repair and neuroprotection under specific spatiotemporal conditions. Combined with advancements in cutting-edge models such as microfluidic chips, we discuss the clinical translation progress of chemokine research, including potential biomarkers and targeted therapeutic strategies, and propose precise breakthrough paths for the two core challenges of network redundancy and spatiotemporal heterogeneity. Finally, we construct a complete research framework for chemokine-mediated regulation of NVU homeostasis, providing novel insights and directions for restoring BBB function and treating intractable neurological diseases.