CCL11 Differentially Affects Post-Stroke Brain Injury and Neuroregeneration in Mice Depending on Age

Summary

Background Chemokine C-C motif ligand 11 (CCL11/eotaxin-1), traditionally known for recruiting eosinophils in allergic responses, has recently emerged as a significant factor in neurological conditions. Studies have implicated CCL11 in neurogenesis and neuroinflammation, with evidence showing it promotes neuroregeneration in neonatal mice after stroke. Stroke-induced brain injury causes significant neurological deficits and represents a major global health burden. While CCL11's neuroprotective effects are documented in neonatal models, its impact on the adult ischemic brain remains poorly understood, particularly whether these effects vary with age—an important consideration given the different regenerative capacities throughout life. This study investigates the age-dependent effects of CCL11 on post-stroke brain injury and neuroregeneration by comparing outcomes in adolescent and adult mice, potentially informing age-specific therapeutic strategies for stroke recovery. Methods The researchers induced cerebral ischemia in adolescent (six-week-old) and adult (six-month-old) C57BL6 mice by occluding the middle cerebral artery for 45 minutes, followed by reperfusion. CCL11 was administered intraperitoneally at the onset of reperfusion and daily for seven consecutive days. The team assessed acute brain injury, neurological recovery over 28 days, neurogenesis, gliogenesis, and immune cell infiltration in both age groups. Additionally, the CCL11 inhibitor SB297006 was used to evaluate the potential for mitigating CCL11's effects. Findings and Implications In adult mice, CCL11 administration resulted in larger infarct volumes and impaired neurological recovery over 28 days. Conversely, adolescent mice did not exhibit increased acute brain injury following CCL11 treatment. Notably, CCL11 enhanced neurogenesis and gliogenesis in adolescent mice but had no such effect in adults. Flow cytometry revealed that CCL11 modified immune responses differently across age groups: in adolescents, there was increased migration of microglia, B cells, and T cells into the brain, whereas in adults, only B cell numbers increased. Importantly, the CCL11 inhibitor SB297006 effectively reversed these effects. This study identifies CCL11 as a significant mediator of secondary cell injury post-stroke, with age-dependent effects on neuroregeneration and immune response. Targeting the CCL11 pathway, particularly with inhibitors like SB297006, may offer novel therapeutic strategies for stroke treatment, tailored to the patient's age.