CCR3 inhibition suppresses inflammation-driven recruitment of peripheral immune cells to the eye

Abstract

C-C chemokine receptor type 3 (CCR3) has been linked with age-related macular degeneration (AMD) pathologies. Specifically, its function as an immune modulator in AMD remains unclear. To address this question, we investigated the impact of CCR3 inhibition on inflammation, a key driver of AMD pathologies, by assessing inflammatory cytokines and infiltrating immune cells in two models of ocular inflammation.Mice were orally dosed twice a day with AKST4290, a CCR3 small molecular inhibitor, in the sodium iodate (NaIO3) and myelin oligodendrocyte glycoprotein (MOG) models. A combination of autoradiography and analytical chemistry techniques were used to assess drug concentration and distribution. Bead-based multiplexing technology was used to determine cytokine concentrations, and flow cytometry and immunohistochemistry was used to ascertain ocular immune-cell composition.CCR3 expression was detected in the retinal pigment epithelium (RPE)/choroid complex where AKST4290 was found to preferentially accumulate at sustained levels. In the NaIO3model, inhibition of CCR3 with AKST4290 significantly decreased both the concentration of specific chemokines and the number of multiple populations of infiltrating peripheral immune cell. Furthermore, effects of CCR3 inhibition on immune cell infiltration were confirmed in the MOG model.These data demonstrate that CCR3 inhibition strongly modulates local inflammation by impacting both cytokine concentrations and immune cell composition in ocular diseases.Moreover, these findings together with the known role of CCR3 in promoting pathologic angiogenesis implicate a pleiotropic role for CCR3 in AMD.