The microglial inhibitory receptor CD200R1 as a candidate target to control neuroinflammation

Abstract

Microglia are the main endogenous immune cells of the central nervous system. In response to noxious stimuli, they develop reactive phenotypes to re-establish cerebral homeostasis and minimize neuronal damage. However, reactive microglia produce pro-inflammatory factors with potential neurotoxic effects. Consequently, progress and resolution of microglial activation have to be tightly controlled to avoid negative secondary effects. Neuronal signals play a relevant role in the control of microglial activation. Among them, inhibitory mechanisms such as CD200 ligand (neuronal)-CD200R1 receptor (microglial) interaction, maintain under control the microglia inflammatory phenotype in physiological conditions. Alterations in CD200 and CD200R1 expression have been described in neurodegenerative diseases. The aim of the present work was to study the effect of CD200R1 modulation on microglia reactive phenotype using experimental in vitro approaches. Glial cell cultures were treated with a proinflammatory stimulus (LPS+IFN-γ) and the pattern of expression of pro- and anti-inflammatory molecules was determined in the absence and presence of CD200R1 overexpression, CD200R1 stimulation and CD200R1 inhibition. CD200R1 overexpression resulted in a reduced induction of the expression of pro-inflammatory cytokines and enzymes and a strong induction of IL-10 expression in BV2 microglial cells. The induction of the expression of pro-inflammatory molecules was inhibited in reactive primary microglial cells treated with a CD200R1 agonist, while the expression of antiinflammatory molecules was enhanced. Finally, inhibition of CD200-CD200R1 interaction in mixed glial cultures potentiated the pro-inflammatory response. Thus, the reactive phenotype of glial cells can be modulated through an action on CD200R1 expression or stimulation, suggesting CD200R1 as a candidate target to act against neuroinflammation in neurodegenerative diseases