CSF1R antagonism limits local restimulation of antiviral CD8+ T cells during viral encephalitis

Kristen E Funk,Robyn S Klein

doi:10.1186/s12974-019-1397-4

Abstract

BackgroundMicroglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling. Microglial depletion via CSF1R inactivation improves cognition in mouse models of neuroinflammation, but limits virologic control in the CNS of mouse models of neurotropic infections by unknown mechanisms. We hypothesize that CSF1R plays a critical role in myeloid cell responses that restrict viral replication and locally restimulate recruited antiviral T cells within the CNS.MethodsThe impact of CSF1R signaling during West Nile virus infection was assessed in vivo using a mouse model of neurotropic infection. Pharmacological inactivation of CSF1R was achieved using PLX5622 prior to infection with virulent or attenuated strains of West Nile virus (WNV), an emerging neuropathogen. The subsequent effect of CSF1R antagonism on virologic control was assessed by measuring mortality and viral titers in the CNS and peripheral organs. Immune responses were assessed by flow cytometric-based phenotypic analyses of both peripheral and CNS immune cells.ResultsMice treated with CSF1R antagonist prior to infection exhibited higher susceptibility to lethal WNV infection and lack of virologic control in both the CNS and periphery. CSFR1 antagonism reduced B7 co-stimulatory signals on peripheral and CNS antigen-presenting cells (APCs) by depleting CNS cellular sources, which limited local reactivation of CNS-infiltrating virus-specific T cells and reduced viral clearance.ConclusionsOur results demonstrate the impact of CSF1R antagonism on APC activation in the CNS and periphery and the importance of microglia in orchestrating the CNS immune response following neurotropic viral infection. These data will be an important consideration when assessing the benefit of CSF1R antagonism, which has been investigated as a therapeutic for neurodegenerative conditions, in which neuroinflammation is a contributing factor.

Highlights

Microglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling
CSF1R antagonism depletes myeloid populations within peripheral blood and CNS CSF1R signaling is essential for the development of mononuclear phagocytes including microglia, but pharmacological antagonism has been reported to selectively deplete microglia [48]
Specificity of P2RY12 for CNS-resident microglia is demonstrated by lack of staining in leukocytes isolated from peripheral immune compartments (Additional file 1 G–O)

Summary

Introduction

Microglia are resident macrophages of the central nervous system (CNS) locally maintained through colony-stimulating factor 1 receptor (CSF1R) signaling. Microglial depletion via CSF1R inactivation improves cognition in mouse models of neuroinflammation, but limits virologic control in the CNS of mouse models of neurotropic infections by unknown mechanisms. In addition to a multitude of homeostatic functions throughout development and healthy aging [10, 11], microglia participate in both innate and adaptive immune responses through recognition of pathogen-associated molecular patterns and damage-associated molecular patterns [12], which stimulate morphological changes [13, 14] and increase production of reactive oxidative species [15, 16] and cytokines/chemokines [17, 18]. Mice lacking either CD8+ T cells or MHC-I molecules have higher CNS viral burdens, increased mortality after infection, and prolonged viral persistence, suggesting that cell-mediated immunity controls virus within the CNS [32]

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