Recombinant CCL17 Shifts Microglial Phenotype and Protects Neurons from Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) Injury

Ischemic stroke is a leading cause of death and disability worldwide, characterized by complex neuroinflammatory processes. Microglia serve as the innate immune cells within the central nervous system and are central mediators of neuroinflammatory responses. We investigated whether recombinant CCL17 (rCCL17) could influence microglial polarization and exert neuroprotective effects under OGD/R-induced injury conditions. Using brain tissue from neonatal mice, primary microglia were obtained and validated through morphological examination and immunofluorescence detection of IBA-1 and CD206. MTT assays revealed that microglial viability decreased significantly following prolonged hypoxia, establishing a 4-hour OGD with 24-hour reoxygenation as the experimental paradigm. Exposure to OGD/R conditions induced a marked increase in M1-associated genes—CD16, CD32, and iNOS—in microglia, whereas M2 markers like CD206, Arg-1, and IL-10 exhibited minimal upregulation. Notably, rCCL17 treatment at 150 ng/mL mitigated this pro-inflammatory response, facilitating a shift toward the M2 phenotype with elevated expression of associated markers. Furthermore, LPS stimulation led to increased M1 marker expression and a reduction in M2 markers, an effect that was reversed by rCCL17 treatment, except for IL-10. To assess the impact of rCCL17 on neuronal survival, primary neurons were subjected to OGD/R, revealing significant cell death after 4 h of hypoxia. rCCL17 at 100 ng/mL and 150 ng/mL significantly improved neuronal viability. When neurons were co-cultured with rCCL17-pretreated microglia, neuronal viability was significantly improved. Western blot analysis further confirmed that rCCL17-pretreated microglia reduced cleaved caspase-3 levels in neurons, indicating an anti-apoptotic effect. These results point to CCL17 as a modulator of microglial polarization, dampening M1-related responses and favoring M2-associated functions, thereby exerting neuroprotective effects under ischemic conditions. Evidence from this work suggests that CCL17 could be developed as an effective treatment for ischemic stroke.

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Recombinant CCL17 Shifts Microglial Phenotype and Protects Neurons from Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) Injury

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