Mechanisms of leukocyte migration across the blood–retina barrier

Immune-mediated inflammation in the retina is regulated by a combination of anatomical, physiological and immuno-regulatory mechanisms, referred to as the blood–retina barrier (BRB). The BRB is thought to be part of the specialised ocular microenvironment that confers protection or “immune privilege” by deviating or suppressing destructive inflammation. The barrier between the blood circulation and the retina is maintained at two separate anatomical sites. These are the endothelial cells of the inner retinal vasculature and the retinal pigment epithelial cells on Bruch’s membrane between the fenestrated choroidal vessels and the outer retina. The structure and regulation of the tight junctions forming the physical barrier are described. For leukocyte migration across the BRB to occur, changes are needed in both the leukocytes themselves and the cells forming the barrier. We review how the blood–retina barrier is compromised in various inflammatory diseases and discuss the mechanisms controlling leukocyte subset migration into the retina in uveoretinitis in more detail. In particular, we examine the relative roles of selectins and integrins in leukocyte interactions with the vascular endothelium and the pivotal role of chemokines in selective recruitment of leukocyte subsets, triggering adhesion, diapedesis and migration of inflammatory cells into the retinal tissue

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

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

Retinal microenvironment controls resident and infiltrating macrophage function during uveoretinitis

PURPOSE. Macrophages infiltrating an inflamed or injured tissue undergo development of coordinated sets of properties that contribute to tissue damage, repair, and remodeling. The purpose of this study was to determine whether macrophages isolated from normal or inflamed retina are programmed to a distinct set of properties and to examine whether the development of experimental autoimmune uveoretinitis (EAU) affects macrophage function. METHODS. EAU was induced in Lewis rats, and a retina-derived macrophage–enriched population was generated by density centrifugation during the prepeak, peak, and resolution phases of the disease. Cell surface phenotype was assessed by twoand three-color flow cytometry, and function was determined in vitro by nitric oxide (NO) production, with or without further cytokine stimulation or by immunohistochemistry t

Blocking antibodies to CD62L, CD44, and PSGL-1 significantly reduced rolling and sticking of monocytes in inflamed vessels

Freshly isolated EGFP bone marrow–derived monocytes (8 × 10) were injected intravenously into mice immunized 21 to 24 days previously with peptide to induce EAU. After 48 hours, cell trafficking in the retinal vasculature was analyzed by SLO. Retinal images were recorded for 15 minutes, and then mice were injected intravenously with 30 μg/mouse of rat anti–mouse antibody, and recording continued for a further 20 minutes. Data were then compared before and after antibody treatment. (A) Recirculation of adoptively transferred cells was expressed as the number of transferred EGFP monocytes detected in the same section of the retinal vessel before and after antibody infusion. (B) Rolling efficiency, expressed as the percentage of rolling fluorescent cells among the total number of fluorescent cells entering a venule before and after antibody infusion. (C) Sticking efficiency, expressed as the percentage of fluorescent monocytes within the same venule that remained adherent for at least 20 seconds. * < .05; ** < .01; Student paired test; n was at least 16 vessels from 3 mice.<p><b>Copyright information:</b></p><p>Taken from "Critical but divergent roles for CD62L and CD44 in directing blood monocyte trafficking in vivo during inflammation"</p><p></p><p>Blood 2008;112(4):1166-1174.</p><p>Published online 15 Aug 2008</p><p>PMCID:PMC2515150.</p><p>© 2008 by The American Society of Hematology</p