CCR3 plays a role in murine age-related cognitive changes and T-cell infiltration into the brain

Abstract

Targeting immune-mediated, age-related, biology has the potential to be a transformative therapeutic strategy. However, the redundant nature of the multiple cytokines that change with aging requires identification of a master downstream regulator to successfully exert therapeutic efficacy. Here, we discovered CCR3 as a prime candidate, and inhibition of CCR3 has pro-cognitive benefits in mice, but these benefits are not driven by an obvious direct action on central nervous system (CNS)-resident cells. Instead, CCR3-expressing T cells in the periphery that are modulated in aging inhibit infiltration of these T cells across the blood-brain barrier and reduce neuroinflammation. The axis of CCR3-expressing T cells influencing crosstalk from periphery to brain provides a therapeutically tractable link. These findings indicate the broad therapeutic potential of CCR3 inhibition in a spectrum of neuroinflammatory diseases of aging.

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

“…Furthermore, we validated the impact of CCR3 inhibition on the recruitment of T cells in the MOG model (Fig 5). These results are consistent with the observed effects of CCR3 inhibition by AKST4290 in reducing the number of T cells in the brain in the MOG model [23].…”

“…An immune reaction was generated against myelin with M. Tuberculosis H37 Ra and pertussis toxin in a similar fashion to experimental autoimmune encephalomyelitis (EAE) induction [25]. On an abbreviated time course, in comparison to EAE, this technique has been shown to robustly mobilize T cells to myelin containing regions such as the CNS and we refer to this model as MOG (myelin oligodendrocyte glycoprotein) [23]. Thus the MOG model does not recapitulate AMD but rather allows for validation of the robust effect CCR3 inhibition has on a specific feature of the immune response in AMD.…”

“…Interestingly, a recent study by Rege et al reported that multiple CCR3 ligands including CCL11 increase in the mouse brain with age; and inhibition of CCR3 with orally-dosed AKST4290 was demonstrated to reduce the age-dependent increase in T cells in the brain [23,39]. They confirmed that peripheral T cells do indeed express CCR3 and went on to reveal that CCR3 expression in the brain was limited to a very small proportion of microglia.…”

“…To elucidate the role of CCR3 in modulating inflammation in the eye, we investigated the effects of CCR3 inhibition in two mouse models of ocular inflammation: sodium iodate (NaIO 3 ) and myelin oligodendrocyte glycoprotein (MOG) [22,23]. First, we used a combination of autoradiography and analytical chemistry techniques to assess AKST4290 concentration and distribution in the mouse eye.…”

Anti-CD49d Antibody Treatment Improves Survival and Attenuates Neurocognitive Deficits after Traumatic Brain Injury in Aged Mice

“…Similarly, other studies have found that aged microglia in the subventricular zone upregulate Ccl5 and Ccl2 to recruit CCR3-expressing T cells (13). Inhibiting CCR3 in T cells attenuates this T-cell migration into the brain and alleviates microgliosis in aged mouse brains (14). In line with current literature, previous work in our laboratory indicated that microglia from aged mouse brains demonstrate more significant levels of activation after TBI than microglia from young mouse brains after TBI (6).…”