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Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during
Cathryn Broderick1, Robert M Hoek, John V Forrester
1Department of Ophthalmology, University of Aberdeen, United Kingdom.
Abstract:
Recent evidence supports the notion that tissue OX2 (CD200) constitutively provides down-regulatory signals to myeloid-lineage cells via CD200-receptor (CD200R). Thus, mice lacking CD200 (CD200(-/-)) show increased susceptibility to and accelerated onset of tissue-specific autoimmunity. In the retina there is extensive expression of CD200 on neurons and retinal vascular endothelium. We show here that retinal microglia in CD200(-/-) mice display normal morphology, but unlike microglia from wild-type CD200(+/+) mice are present in increased numbers and most significantly, express inducible nitric oxide synthase (NOS2), a macrophage activation marker. Onset and severity of uveitogenic peptide (1-20) of interphotoreceptor retinoid-binding protein-induced experimental autoimmune uveoretinitis is accelerated in CD200(-/-) mice and although tissue destruction appears no greater than seen in CD200(+/+) mice, there is continued increased ganglion and photoreceptor cell apoptosis. Myeloid cell infiltrate was increased in CD200(-/-) mice during experimental autoimmune uveoretinitis, although NOS2 expression was not heightened. The results indicate that the CD200:CD200R axis regulates retinal microglial activation. In CD200(-/-) mice the release of suppression of tonic macrophage activation, supported by increased NOS2 expression in the CD200(-/-) steady state accelerates disease onset but without any demonstration of increased target organ/tissue destruction.
Insights
The CD200:CD200R pathway regulates retinal microglia. Mice lacking CD200 show accelerated autoimmune uveoretinitis onset due to increased microglial activation and nitric oxide synthase 2 expression.
Area of Science:
- Immunology
- Neuroscience
- Ophthalmology
Background:
- Tissue OX2 (CD200) signaling via CD200-receptor (CD200R) down-regulates myeloid cells.
- CD200 knockout mice exhibit heightened susceptibility and earlier onset of autoimmune diseases.
- The retina expresses CD200 on neurons and vascular endothelium.
Purpose of the Study:
- To investigate the role of the CD200:CD200R axis in regulating retinal microglial activation.
- To determine the impact of CD200 deficiency on experimental autoimmune uveoretinitis (EAU) in mice.
Main Methods:
- Comparative analysis of retinal microglia in CD200 knockout (CD200(-/-)) and wild-type (CD200(+/+)) mice.
- Induction of experimental autoimmune uveoretinitis using interphotoreceptor retinoid-binding protein peptide (1-20).
- Assessment of microglial morphology, number, inducible nitric oxide synthase (NOS2) expression, myeloid cell infiltration, and apoptosis in retinal cells.
Main Results:
- Retinal microglia in CD200(-/-) mice showed increased numbers and expressed NOS2, a macrophage activation marker, unlike in CD200(+/+) mice.
- EAU onset and severity were accelerated in CD200(-/-) mice, with increased ganglion and photoreceptor cell apoptosis.
- While myeloid cell infiltration increased during EAU in CD200(-/-) mice, NOS2 expression was not further heightened.
Conclusions:
- The CD200:CD200R axis is critical for regulating retinal microglial activation.
- Loss of CD200 signaling leads to tonic microglial activation, evidenced by increased NOS2 expression, accelerating autoimmune uveoretinitis onset.
- Accelerated disease in CD200(-/-) mice occurs without increased ocular tissue destruction, suggesting a modulation of inflammatory response rather than exacerbation of damage.