Constitutive Retinal CD200 Expression Regulates Resident Microglia and Activation State of Inflammatory Cells during Experimental Autoimmune Uveoretinitis

Broderick, Cathryn; Hoek, Robert M.; Forrester, John V.; Liversidge, Janet; Sedgwick, Jonathon D.; Dick, Andrew D.

doi:10.1016/s0002-9440(10)64444-6

Cited by 190 publications

(160 citation statements)

References 27 publications

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“…It was reported that microglia exhibited morphological signs of activation in spinal cord of CD200 Ϫ/Ϫ mice, whereas facial nerve transection induced an accelerated microglial activation. CD200 Ϫ/Ϫ mice also have more profound clinical signs in experimental autoimmune encephalitis (Hoek et al, 2000) and accelerated disease progression in experimental autoimmune uveoretinitis (Broderick et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

CD200 Ligand–Receptor Interaction Modulates Microglial ActivationIn VivoandIn Vitro: A Role for IL-4

Lyons¹,

Downer²,

Crotty³

et al. 2007

J. Neurosci.

226

242

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Deficits in cognitive function are associated with neuroinflammatory changes, typified by activation of glial cells and an alteration of the pro-and anti-inflammatory cytokine balance in the brain. Although there is evidence to suggest that activation of microglia is regulated by interaction with other cell types in the brain, the mechanism(s) involved is poorly understood. Here, we provide evidence that interaction between CD200 and its receptor plays a role in modulating microglial activation under conditions of chronic and acute inflammation of the brain. We report that interleukin-4 (IL-4) plays a central role in modulating expression of CD200 and identify a mechanism by which IL-4 directly controls microglial cell activation. Our findings provide the first demonstration of a role for IL-4 in modulating CD200 expression and suggest a mechanism for regulation of microglial activation in the intact CNS under inflammatory conditions.

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Section: Discussionmentioning

confidence: 99%

CD200 Ligand–Receptor Interaction Modulates Microglial ActivationIn VivoandIn Vitro: A Role for IL-4

Lyons¹,

Downer²,

Crotty³

et al. 2007

J. Neurosci.

226

242

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show abstract

“…CD200 is ubiquitously expressed on macrophages, neurons, and endothelium, [10][11][12][13] and perturbing their interaction results in an aggressive disease phenotype. 14,15 If we attempt to reconstitute and de-activate macrophage function (by direct ligation of CD200R with anti-CD200R monoclonal antibodies or by a CD200Fc), attenuation of retinal or CNS inflammation can be achieved 14,16 as well as regulation of other myeloid cells, including mast cells in the lung. [17][18][19][20] How do we keep the peace?…”

Section: Keeping the Peacementioning

confidence: 99%

Doyne lecture 2016: intraocular health and the many faces of inflammation

Dick

2016

Eye

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Dogma for reasons of immune privilege including sequestration (sic) of ocular antigen, lack of lymphatic and immune competent cells in the vital tissues of the eye has long evaporated. Maintaining tissue and cellular health to preserve vision requires active immune responses to prevent damage and respond to danger. A priori the eye must contain immune competent cells, undergo immune surveillance to ensure homoeostasis as well as an ability to promote inflammation. By interrogating immune responses in non-infectious uveitis and compare with age-related macular degeneration (AMD), new concepts of intraocular immune health emerge. The role of macrophage polarisation in the two disorders is a tractable start. TNF-alpha regulation of macrophage responses in uveitis has a pivotal role, supported via experimental evidence and validated by recent trial data. Contrast this with the slow, insidious degeneration in atrophic AMD or in neovasular AMD, with the compelling genetic association with innate immunity and complement, highlights an ability to attenuate pathogenic immune responses and despite known inflammasome activation. Yolk sac-derived microglia maintains tissue immune health. The result of immune cell activation is environmentally dependent, for example, on retinal cell bioenergetics status, autophagy and oxidative stress, and alterations that skew interaction between macrophages and retinal pigment epithelium (RPE). For example, dead RPE eliciting macrophage VEGF secretion but exogenous IL-4 liberates an anti-angiogenic macrophage sFLT-1 response. Impaired autophagy or oxidative stress drives inflammasome activation, increases cytotoxicity, and accentuation of neovascular responses, yet exogenous inflammasome-derived cytokines, such as IL-18 and IL-33, attenuate responses.

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“…41,42 In vivo studies in EAU, particularly of CD200 À/À mice, suggest that the interaction of CD200 with its receptor delivers inhibitory signals to myeloid cells via CD200R. 43,44 As a result, the retina's resident CD200R þ macrophages (microglia) remain tonically deactivated patrolling and governing retinal homeostasis. 45 On the other side of the fence, complement activation will also generate further macrophage activation via C5a, promoting and promulgating the pro-inflammatory macrophage status.…”

Section: Understanding Immunopathologymentioning

confidence: 99%

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

Lee

Dick

2011

Eye

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The blockbuster drug paradigm is under increasing scrutiny across the biopharmaceutical industry. Intraocular inflammation poses particular challenges to this, given the heterogeneity of conditions in the uveitis spectrum, and the increasing acknowledgement of individual patient and disease variance in underlying immune responses. This need has triggered a drive towards personalised and stratified medicine, supported and enabled as a result of continued development of both experimental models and molecular biological techniques and improved clinical classification. As such we have the ability now to systematically appraise at a genomic, transcriptomic, and proteomic level individual immunophenotype, and the promise that in the eye this can be augmented by in vivo immune imaging to identify individual immunopathology. With such advances all running in parallel, we are entering an era of experimental medicine that will facilitate early diagnosis, generate biomarkers for accurate prognostication, and enable the development of individualised and targeted therapies, which can progress rapidly into clinical practice.

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Constitutive Retinal CD200 Expression Regulates Resident Microglia and Activation State of Inflammatory Cells during Experimental Autoimmune Uveoretinitis

Cited by 190 publications

References 27 publications

CD200 Ligand–Receptor Interaction Modulates Microglial ActivationIn VivoandIn Vitro: A Role for IL-4

CD200 Ligand–Receptor Interaction Modulates Microglial ActivationIn VivoandIn Vitro: A Role for IL-4

Doyne lecture 2016: intraocular health and the many faces of inflammation

Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

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