Immunomodulator CD200 Promotes Neurotrophic Activity by Interacting with and Activating the Fibroblast Growth Factor Receptor

Abstract

The CD200 ligand is expressed by a variety of cell types, including vascular endothelia, kidney glomeruli, some subsets of T and B cells, and neurons in the brain and periphery. In contrast, the receptor of CD200, CD200R, has a limited expression pattern and is mainly expressed by cells of myeloid origin. A recently solved crystal structure of the CD200-CD200R ectodomain complex suggests involvement of the first immunoglobulin (Ig)-like modules in ligand-receptor binding, resulting in the inhibition of myeloid cell function. In the central nervous system, CD200 has been implicated in the suppression of microglia activation. We for the first time demonstrated that CD200 can interact with and transduce signaling through activation of the fibroblast growth factor receptor (FGFR), thereby inducing neuritogenesis and promoting neuronal survival in primary neurons. CD200-induced FGFR phosphorylation was abrogated by CD200R, whereas FGF2-induced FGFR activation was inhibited by CD200. We also identified a sequence motif located in the first Ig-like module of CD200, likely representing the minimal CD200 binding site for FGFR. The FGFR binding motif overlaps with the CD200R binding site, suggesting that they can compete for CD200 binding in cells that express both receptors. We propose that CD200 in neurons functions as a ligand of FGFR.

The Potential Role of Dysfunctions in Neuron-Microglia Communication in the Pathogenesis of Brain Disorders

“…As shown by Webb and Barclay [ 143 ], CD200 appears on neuronal bodies and axons, where it is involved in axonal extension [ 143 , 144 ]. CD200 plays a role in the process of anxiogenic sprouting and elongation, in addition to synapse formation [ 145 ] and neuritogenesis, which involves the interaction and activation of the fibroblast growth factor receptor [ 146 ]. The role of CD200 in the oligodendrogenesis recovery mechanism was also demonstrated, as the ligand may promote this process [ 147 ].…”

Dysregulated fibroblast growth factor (FGF) signaling in neurological and psychiatric disorders

“…The membrane glycoprotein CD200 can directly interact with FGFR1. The oxifin1 peptide derived from CD200 mimicked its neuritogenic and survival-promoting effects [96]. Proteins of the cell adhesion molecule (CAM) family, such as nectin-1, can also bind and activate FGF receptors [97].…”

Prognostic impact of CD200 and CD56 expression in adult acute lymphoblastic leukemia patients

“…However, CD200 has a central role in immune tolerance that protects stem cells and other critical tissues from immune damage [7]. CD200 can induce neurogenesis and promote neuronal survival in primary neurons through activation of the fibroblast growth factor receptor (FGFR) [9]. CD200 with its receptor CD200R delivers an inhibitory signal to the target cell in most circumstances [10] and imparts an immunosuppressive signal leading to the inhibition of macrophage function [11], induction of regulatory T cells [12], switching of cytokine profiles from Th1 to Th2 and inhibition of tumorspecific T-cell immunity [13].…”