A potential monocyte-regulatory T cell axis in neurorestoration following ischemic stroke

Abstract

Abstract Neurorestoration following ischemic stroke is regulated by a complex interaction between the resident glial cells and the immune cells infiltrated to the brain. Using transient middle cerebral artery occlusion (tMCAO), it was shown that both monocytes and regulatory T cells (Tregs) play a critical role in facilitating neurorestoration following ischemic injury of the brain. However, the underlying mechanisms are not well-understood. Importantly, it is unclear whether the neurorestorative effect of monocytes and Tregs require their cognate interaction. The goal of this study is to investigate the interplay between monocytes and Tregs in facilitating brain recovery following ischemic injury. Using mouse tMCAO model, we found that 1) Monocytes were present in the brain both at the sub-acute (day 3) and chronic phases (day 14) following tMCAO, whereas Tregs were significantly increased in the brain only at the chronic phase. 2) During the chronic phase, monocytes and Tregs interacted within the glial scar. 3) CCR2, which controls monocyte trafficking, was expressed in monocytes but not in Tregs, but the number of both monocytes and Tregs were substantially reduced following tMCAO when CCR2 was deleted. 4) CCR2-deficient mice had a reduced survival rate and a larger area of glia scar during the chronic phase post-stroke compared to CCR2-sufficient mice. 5) Tregs in the cervical lymph nodes expressed CCR4 following tMCAO, which is known to control Treg trafficking. 6) Monocytes express CCR4 ligands, CCL17 and CCL22, during differentiation into monocyte-derived cells (MDCs) in vitro. Thus, our data demonstrate that monocytes may exert their neuroprotective via the regulation of Treg trafficking and/or expansion following ischemic stroke. This work was supported by NIH grants P20GM109098 and R21NS125056 to Edwin Wan. Kelly Monaghan was supported through The American Association of Immunologists Careers in Immunology Fellowship Program.