Decoding the spatiotemporal pleiotropy of CCL2-CCR2 signaling to guide staged therapies in CNS injury

Objective (Background) Intracerebral hemorrhage (ICH) and other acute central nervous system (CNS) injuries share a devastating pathological hallmark: neuroinflammation. Within this complex immune network, the CCL2-CCR2 signaling axis emerges as a critical driver connecting local tissue damage to systemic immune mobilization. However, the translational stagnation of CCL2-CCR2-targeted therapies—and the failure of broad-spectrum CCR2 blockade in non-CNS clinical trials—highlights that such static inhibition fundamentally ignores the dynamic, stage-specific shifting of myeloid phenotypes. Methods To address this bottleneck, our review delineates the spatiotemporal evolution of CCL2-CCR2 signaling, anchored primarily in hemorrhagic stroke pathophysiology, while utilizing ischemic, traumatic, and spinal cord injuries as comparative models. Results Following acute hemorrhagic or ischemic insults, rapidly upregulated CCL2 recruits peripheral monocytes, exacerbating secondary damage by promoting barrier disruption, oxidative stress, and iron-induced ferroptosis. Furthermore, we evaluate emerging precision-targeted interventions designed to bypass current limitations, including allosteric biased modulators, biomimetic nanodelivery platforms, and targeted transcriptional silencing. Conclusion Ultimately, we propose that dynamically staged immunomodulatory strategies are required to effectively balance early neuroprotection with late-stage hematoma clearance and tissue regeneration