Pericyte-Macrophage Interactions Maintain CNS Immune Tolerance

点击翻译按钮获取中文摘要

Pericyte-Macrophage Interactions Maintain CNS Immune Tolerance ABSTRACT Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) where infiltrating T cells ultimately lead to the destruction of myelin. T cells initially accumulate in the perivascular space of the brain and the meninges where they must interact with antigen presenting cells prior to activating and infiltrating into the parenchyma. This suggests immune interactions in the perivascular space may serve as a checkpoint and determine the fate of infiltrating T cells. Macrophages and pericytes are two important cells in the perivascular space of the brain and meninges. Under homeostatic conditions, border macrophages have an immuno- surveillant phenotype and express surface markers typical for macrophages that help with healing tissues. The signals that maintain CNS border macrophages in this state are unknown. Pericytes also reside in the perivascular space and are a key component of the neurovascular unit where they regulate blood flow, angiogenesis, the blood-brain barrier (BBB), and neuroinflammation. Although each cell type has be implicated in multiple sclerosis (MS), the communication between the 2 cell types has not been described. Our preliminary data demonstrate that cultured pericytes suppress the activation of T cells through engaging macrophages. Pericytes directly contact macrophages and reprogram them to downregulate genes need for antigen presentation and T cells activation. Pericytes/macrophage interactions are mediated by lipoprotein receptor- related proteins (LRP) on macrophages and dependent on p-bodies in pericytes. P-bodies are membrane-less, cytoplasmic organelles that contain mRNAs enriched in regulatory functions. In vivo, pericytes reside in close proximity to perivascular and meningeal macrophages and have the potential to interact closely with macrophages. When we deleted pericytes in vivo, CNS antigen specific T cells infiltrate the perivascular space of the meninges in a manner that was dependent on macrophages. T cells further infiltrate into the parenchyma when triggered by a second signal from the parenchymal. We hypothesize that under homeostatic conditions pericytes communicate with perivascular and meningeal macrophages to maintain them in an immunosuppressive and surveillant state. This contributes to the immuno- privileged nature of the brain. In MS, we hypothesize that communication between pericytes and macrophages breakdown and this unleashes CNS macrophages into a proinflammatory state that contributes to T cell activation and infiltration into the brain. In this proposal, we will determine if pericytes instruct perivascular macrophages to inhibit brain-specific T cells from entering the parenchyma, investigate whether pericytes reprogram CNS macrophages in vivo, and determine if macrophages must engulf components of pericytes in order to be reprogramed to suppress T cells. Overall, this proposal will investigate an unexplored interaction between pericytes and CNS border macrophages.