AKST4290, a CCR3 Inhibitor, Reduces Age-Related Inflammation and Immune Cell Infiltration

Abstract

Abstract Eotaxin, a potent pro-inflammatory mediator, is a chemokine whose levels in plasma increase with age. CCR3, the primary receptor for eotaxin, is expressed on immune cells such as eosinophils and subsets of T lymphocytes, making it a potential therapeutic target for age-related inflammation. Using the CCR3 selective antagonist AKST4290 we aimed to assess the effects of modulating eotaxin/CCR3 signaling in mouse models of aging, inflammation and peripheral immune cell infiltration. In an aging model, using 18-month-old C57BL/6 mice, AKST4290 treatment reverted the increased blood levels of immune cells to those seen in young mice, with no effects on immune cell levels in young mice. In inflammation models, using either 8-week-old SKH1-Elite mice challenged with Oxazolone or 8-week-old C57BL/6 mice challenged with LPS, AKST4290 reverted the increased blood levels of immune cells to baseline levels and did not affect cell types unchanged by the stressors. In contrast, Dexamethasone produced a broad, non-specific, decrease of total white blood cells and critical subpopulations. In an immune cell infiltration model, using 8-week-old C57BL/6 mice challenged with experimental autoimmune encephalomyelitis (EAE), AKST4290 significantly decreased EAE-induced T cell infiltration and microgliosis in the brain. These findings suggest that AKST4290 is a potent immunomodulator that normalizes immune cell populations related to inflammation to healthy levels, both in the context of disease and aging. These immune modulatory and anti-inflammatory effects have functional consequences in aging models, indicating its therapeutic potential in multiple age-related disorders.