Thrombospondin-1-Mediated Regulation of Microglia Activation after Retinal Injury
ABSTRACT Thrombospondin (TSP)-1 has been demonstrated to play a vital role in immune privilege. The functional phenotype of ocular antigen-presenting cells that contributes to the immune privilege status of the eye is dependent on their expression of TSP-1. Microglia, the local antigen-presenting cells in the retina, undergo rapid activation in response to injury and have the ability to produce both proinflammatory and regenerative neurotrophic factors. In this study, the authors examined TSP-1 as a potential regulator of these phenotype of microglia activated in response to retinal injury.
Expression of markers associated with activated microglia were examined by immunofluorescent staining and semiquantitative real-time PCR analysis of retina derived from WT or TSP-1 null mice at various time intervals after light- or laser-induced retinal injury.
In the absence of TSP-1, microglia in uninjured retina express major histocompatibility complex class II and migrate to the outer layers of the retina. Constitutively increased expression of activated microglia-derived inflammatory molecules such as TNF-alpha and iNOS is detectable in TSP-1 null retina compared with WT controls. After both light-induced and laser-induced retinal injury, enhanced migration of microglia is detected in TSP-1 null retina, and these microglia express markers associated with a proinflammatory phenotype. Compared with WT retina, TSP-1 null retina fails to recover from the laser-induced injury, resulting in irreversible damage.
TSP-1 supports an anti-inflammatory phenotype of microglia in the retina and promotes recovery from injury.
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ABSTRACT: The original evidence for the existence of immunologically privileged sites in the body was based on the prolonged survival of genetically disparate transplanted tissue in the anterior chamber of the eye. The failure of the immune system to elicit an immune response in this and other such sites constitutes the hallmark of the immune privilege status. The remarkably successful field of corneal transplantation in clinical practice is undoubtedly associated with corneal immune privilege. Several investigations have addressed the regulatory mechanisms governing this phenomenon, which involves a complex interplay between multiple molecular and cellular pathways. Furthermore, the use of various transgenic mouse models has facilitated the identification of critical pathways, which upon disruption can modify the immune privileged status of the eye. Understanding these pathways not only reveals the mechanisms underlying various ocular inflammatory disease conditions, but also has clinical implications for the transplantation field and for the treatment of autoimmunity.Ocular immunology and inflammation 10/2010; 18(5):325-33. DOI:10.3109/09273948.2010.512696 · 1.97 Impact Factor
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ABSTRACT: To assess the impact of thrombospondin 1(TSP1) deficiency on choroidal neovascularization (CNV)and to determine whether administration of a TSP1 antiangiogenic mimetic peptide attenuates CNV. The impact of TSP1 deficiency on laser induced CNV was assessed using wild-type (TSP1 +/+) and TSP1-deficient (TSP1 −/−) mice. Three laser burns were placed in each eye of TSP1 +/+ and TSP1 −/− mice to induce CNV. Intravitreal injection of the TSP1 mimetic peptide was performed on days 1 and 7 postlaser in the mice.For quantitative measurements of neovascularization, intercellular adhesion molecule 2 staining was performed at 14 days postlaser of the choroidal-sclera flat mounts. The recruitment of macrophages to the sites of damage was investigated by immunohistochemistry. The CNV area was measured by intercellular adhesion molecule 2 staining and use of ImageJ software. The TSP1 −/− mice exhibited significantly larger areas of neovascularization on choroidal flat mounts compared with TSP1 +/ mice. This was consistent with enhanced recruitment of macrophages in TSP1 −/− mice compared with TSP1 +/+ mice 3 days postlaser. The development of CNV was significantly attenuated in mice receiving the TSP1 antiangiogenic mimetic peptide compared with those receiving vehicle alone. Deficiency of TSP1 contributes to enhanced choroidal neovascularization. This is consistent with the anti-inflammatory and antiangiogenic activity of TSP1. The TSP1 antiangiogenic peptide was effective in attenuation of CNV. Intravitreal injection of TSP1 antiangiogenic mimetic peptides may provide alternative treatment for CNV.Archives of ophthalmology 01/2012; 130(5):615-20. DOI:10.1001/archopthalmol.2011.1892 · 4.40 Impact Factor
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ABSTRACT: The role of the extracellular matrix protein thrombospondins (TSPs) in promoting synaptogenesis is gaining more and more attention. The binding of TSP1 and TSP2 to their neuronal receptor α2δ1 stimulates excitatory synaptogenesis in the development and injury of the central nervous system; however, the specific cellular localization and expression of TSP1/2 and α2δ1 in normal and damaged retinas is unknown. This, to a certain extent, has restricted the progression of research on the molecular mechanisms triggering synaptic plasticity after retinal injury. Here, the cellular localization and expression of TSP1/2 and their receptor α2δ1 was studied in healthy and damaged adult retina induced by elevated intraocular pressure (IOP) using double immunofluorescence labeling and confocal scanning microscopy. We showed the apparent differential distribution of TSP1 and TSP2 in the adult rat retina. TSP1 was confined to the ganglion cell layer and inner nuclear layer, in which it was preferentially expressed by ganglion cells, bipolar cells and horizontal cells but rarely expressed by glial cells. TSP2 staining was diffusely distributed in GFAP- and GS-immunopositive glial cells and processes in the inner retina. In rat retinas, α2δ1 staining was present in ganglion cells, bipolar cells, partial horizontal cells and amacrine cells and the presynaptic terminals. Müller cells and a minority of astrocytes also expressed α2δ1. On the seventh day of elevated IOP, TSP2 immunoreactivity was greatly increased, and immunopositive processes extended throughout the retinal layer and co-localized with GFAP- and GS-positive glial cells. TSP1 distribution in the retina, however, did not change distinctly. α2δ1-immunopositive processes were also increased on the seventh day after elevated IOP. Our study suggested that in the adult rat retina, TSP2, but not TSP1, secreted by glial cells may be involved in the synaptic plastic process after retinal injury through binding to its neuronal receptor α2δ1.Experimental Eye Research 03/2013; 111. DOI:10.1016/j.exer.2013.03.012 · 2.71 Impact Factor