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Michael Elliott, Xiaoman Li, Xiaowu Gu, Alaina Reagan, Timothy Boyce, Ilya Sluch, Md Nawajes Mandal, Michelle Callegan, Daniel Carr; Paradoxical Role of Caveolin-1 in Retinal Inflammation. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3180.
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© ARVO (1962-2015); The Authors (2016-present)
Recent evidence indicates that caveolin-1 (Cav-1), the signature protein of caveolae membrane microdomains, modulates inflammatory responses and innate immunity. In the uveitic retina, Cav-1 expression is dramatically upregulated, particularly in Müller glial cells (Hauck et al., 2010, Mol Cell Proteomics). However, Cav-1’s role in retinal inflammation has not been rigorously tested. In the current study, we examined the effect of Cav-1 ablation on the sensitivity of the retina to inflammation.
Cav-1 knockout (KO) mice were challenged by intravitreal injection of the Toll-like receptor-4 (TLR4) agonist, lipopolysaccharide (LPS), and inflammation was assessed by flow cytometry, immunohistochemistry, and spectral domain optical coherence tomography. Levels of chemoattractants were determined by multiplex immunoassays. Leukostasis was assessed in retinal flatmounts after perfusion with FITC-labeled Concanavalin A (FITC-ConA). Microarray analysis was performed on Cav-1 KO and control retinas/eyecups and the dataset was analyzed by Gene Set Enrichment Analysis (KEGG pathways, gene ontologies, and Ingenuity Pathway Analysis).
Analysis of microarray data (n = 6) revealed a remarkable upregulation of mRNAs associated with inflammatory processes and innate immune responses. Intravitreal challenge with LPS induced a significant increase in the number of infiltrating bone marrow-derived (CD45hi) cells in Cav-1 KO retinas compared to controls as measured by flow cytometry. Increased leukostasis was visualized by FITC-ConA labeling of retinal flatmounts. Given the role of Cav-1 modulation of TLR signaling, we predicted that Cav-1 ablation would result in enhanced TLR4 signaling. Paradoxically, the protein levels of chemoattractant effectors downstream of TLR4 (monocyte chemotactic protein-1/CCL2, CXCL1/KC, interleukin-6, and interleukin-1b) were all significantly reduced in retinal extracts from Cav-1 KO compared to control mice.
This paradox suggests that Cav-1 modulates inflammatory signaling and leukocyte infiltration through distinct mechanisms. We hypothesize that Cav-1 expression may enhance inflammatory signaling while at the same time supporting the physical properties of the blood-retinal barrier.
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