CD200Fc Attenuates Retinal Glial Responses and RGCs Apoptosis After Optic Nerve Crush by Modulating CD200/CD200R1 Interaction

Abstract

To explore the hypothesis that CD200Fc, a CD200R1 agonist with anti-inflammatory properties, will inhibit retinal glial cells hyperactivation and retinal ganglion cells (RGCs) apoptosis after optic nerve injury. CD200Fc was immediately administered after optic nerve crush (ONC) once by intravitreal injection. Rats were euthanized at 5 days after ONC. The density of RGCs was counted by immunostaining of retina flat mounts for Brn3a. TUNEL assay, immunoblotting analysis of ionized calcium-binding adapter molecule 1(iba1) (microglia marker) and glial fibrillary acidic protein (GFAP) (astrocytes and Müller cells marker), RT-PCR analysis of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), monocyte chemotactic protein 1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-8 and IL-10, ELISA measure protein levels of inflammatory cytokines and western blot analysis of CD200 and CD200R1 were evaluated. CD200Fc treatment suppressed ONC-induced RGCs loss through inhibition of RGCs apoptosis. Additionally, expression of glial cells activation markers GFAP and iba1 and production of pro-inflammatory cytokines (COX-2, iNOS, MCP-1, TNF-α, IL-8) were decreased in CD200Fc treated animals after ONC. Meanwhile, anti-inflammatory cytokine IL-10 was increased by CD200Fc treatment in ONC-induced rat retina. Finally, we found that CD200Fc significantly inhibited ONC-induced increased in expression of CD200 and raised the already high basal CD200R1 expression in the rat retina after ONC. Our results demonstrated that the anti-inflammatory effects of CD200Fc in ONC rats model through inhibited the activation of retinal glial cells via the interaction between CD200 and CD200R1, and the neuroprotective effects of CD200Fc on RGCs thought inhibited its apoptosis.

The antidiabetic drug glibenclamide exerts direct retinal neuroprotection

“…53 Another potential important mechanism of action of glibenclamide could be the upregulation of cd200r1, as its agonist CD200FC significantly protected ganglion cells from apoptosis in a nerve crush model. 54 The up-regulation of Bcl2a1 gene, with a strong antiapoptotic effect is in line with this hypothesis.…”

Microglia in Retinal Degeneration

“…Studies on mice lacking CD200 have reported heightened pro-inflammatory responses in experimental animal models of uveoretinitis and exudative form of age related macular degeneration (38–40). Conversely, enhancement of CD200R signaling ameliorates pathological outcome in optic nerve injury and experimental autoimmune uveoretinitis animal models, suggesting that CD200-CD200R interaction could be an exploitable avenue for therapeutic intervention (39, 41).…”

The CD200/CD200R signaling pathway contributes to spontaneous functional recovery by enhancing synaptic plasticity after stroke

“…CD200, a member of the immunoglobulin superfamily, is widely expressed in neurons, astrocytes, and oligodendrocytes, whereas its receptor (CD200 receptor 1, CD200R1) is expressed in myeloid cells and microglia (the brain-resident myeloid cells) in rodents [12] and also highly expressed by neurons in human according to the Ben Barres database. The interaction between CD200 and CD200R1 is critical for inhibiting microglial activation and localized neuroinflammation during the pathological development of several brain diseases, including Parkinson's disease, optic nerve crush, and germinal matrix hemorrhage [13][14][15]. The CD200/CD200R signaling pathway also participates in synaptic plasticity.…”