CCR3 ANTAGONISM DRIVES NEUROINFLAMMATORY BENEFITS IN AGED MICE

Abstract

Recent research into the proteomic composition of plasma has identified specific circulating factors that increase with age and are directly associated with cognitive decline and neurodegeneration. CCL11 (eotaxin) is one such factor elevated with aging that has been shown to reduce neurogenesis in the dentate gyrus as well as impair hippocampal learning and memory when administered to young mice (Villeda, et al. 2011). Given the increase in CCL11 levels observed in plasma from Alzheimer's disease patients, it is possible that CCL11 plays a role in mechanisms underlying cognitive function in neurodegenerative disease, including neuroinflammation. A CCR3 (CCL11 receptor) antagonist was administered to 23-month-old aged C57Bl/6 mice for 3 weeks to measure its effect on age-dependent neuroinflammation. Immunohistochemical assessment of astrocytes and microglia was performed on brain tissues from mice, and circulating cytokines were measured in the plasma. We then used acute and chronic models of LPS administration in young C57Bl/6 mice to determine the effects of CCR3 inhibition in models of induced neuroinflammation, and again performed immunohistochemical assessment of neuroinflammatory markers. We demonstrate that treatment with a CCR3 antagonist resulted in reduced levels of systemic inflammatory cytokines and decreased neuroinflammation in the hippocampus of aged mice. Additionally, treatment with the antagonist diminished LPS-induced neuroinflammation, significantly reducing activated microglia in the hippocampus. CCL11 plays a significant role in the neuroinflammation associated with aging and neurodegenerative disease. Our findings demonstrate that targeting the CCR3 receptor with an antagonist has therapeutic potential to alleviate associated disease phenotypes.