Alterations in CD200-CD200R1 System during EAE Already Manifest at Presymptomatic Stages

Abstract

In the brain of patients with multiple sclerosis, activated microglia/macrophages appear in active lesions and in normal appearing white matter. However, whether they play a beneficial or a detrimental role in the development of the pathology remains a controversial issue. The production of pro-inflammatory molecules by chronically activated microglial cells is suggested to contribute to the progression of neurodegenerative processes in neurological disease. In the healthy brain, neurons control glial activation through several inhibitory mechanisms, such as the CD200-CD200R1 interaction. Therefore, we studied whether alterations in the CD200-CD200R1 system might underlie the neuroinflammation in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. We determined the time course of CD200 and CD200R1 expression in the brain and spinal cord of an EAE mouse model from presymptomatic to late symptomatic stages. We also assessed the correlation with associated glial activation, inflammatory response and EAE severity. Alterations in CD200 and CD200R1 expression were mainly observed in spinal cord regions in the EAE model, mostly a decrease in CD200 and an increase in CD200R1 expression. A decrease in the expression of the mRNA encoding a full CD200 protein was detected before the onset of clinical signs, and remained thereafter. A decrease in CD200 protein expression was observed from the onset of clinical signs. By contrast, CD200R1 expression increased at EAE onset, when a glial reaction associated with the production of pro- and anti-inflammatory markers occurred, and continued to be elevated during the pathology. Moreover, the magnitude of the alterations correlated with severity of the EAE mainly in spinal cord. These results suggest that neuronal-microglial communication through CD200-CD200R1 interaction is compromised in EAE. The early decreases in CD200 expression in EAE suggest that this downregulation might also occur in the initial phases of multiple sclerosis, and that this early neuronal dysfunction might facilitate the development of neuroinflammation. The increased CD200R1 expression in the EAE model highlights the potential use of targeted agonist molecules as therapeutic tools to control neuroinflammation. In summary, the CD200-CD200R1 system is a potential therapeutic target in multiple sclerosis, and CD200R1 agonists are molecules that may be worth developing in this context.

Differences in Intercellular Communication During Clinical Relapse and Gadolinium-Enhanced MRI in Patients With Relapsing Remitting Multiple Sclerosis: A Study of the Composition of Extracellular Vesicles in Cerebrospinal Fluid

“…Glial activation in patients with MS might be due to alterations in neuronal–glial and/or glial–glial crosstalk, and these alterations involve the CD200-CD200R system. The involvement of this pathway in MS pathology was reported by Valente et al In fact, the authors showed that EAE is more severe in CD200 -/- mice than in wild type mice ( Valente et al, 2017 ). In contrast, the attenuated disease observed in EAE Wld s mice was associated with robust constitutive expression of the CD200 molecule on neurons in the CNS compared with control mice ( Chitnis et al, 2007 ).…”

The Central Nervous System Contains ILC1s That Differ From NK Cells in the Response to Inflammation

“…Notably, CD200R expression remained stable on ILC1s during neuroinflammation, making it a suitable candidate to identify them under different inflammatory conditions. The ligand CD200 is expressed by endothelial cells and neurons (40) and the blockage of the CD200R-CD200 axis led to an aggravation of EAE disease (41), while an improved outcome was observed when CD200R activation was enhanced (42). Thus, CD200R + ILC1s could also play a role in mediating anti-inflammatory effects during neuroinflammation.…”

CD200‐CD200R1 signaling pathway regulates neuroinflammation after stroke

“…In contrast, it provoked the expression of proinflammatory factors and suppressed anti‐inflammatory cytokine expression. This was confirmed by many central nervous system studies; in EAE, CD200 and CD200R1 expression was altered at presymptomatic and symptomatic phases in the central nervous system of mice that developed EAE (Valente et al., 2017). In Parkinson's disease (PD) mice, CD200 remarkably suppressed proinflammatory factors, such as IFN‐γ, TNF‐α, and IL‐1β release, and inhibited microglial activation and the release of inflammatory factors to protect dopaminergic (DA) neurons against damage and alleviate PD signs (Lyons et al., 2017; Ren et al., 2016).…”