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Sofia Theodoropoulou, Jian Liu, Dong Li, Damo Xu, Iain McInnes, David A Copland, Andrew D Dick; Interleukin 33/ST2 signaling regulates inflammatory response in choroidal stroma: implications for age-related macular degeneration.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):841.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) is a leading cause of irreversible blindness. Altered immune responses are integral in progression of disease, and in part, in response to oxidative stress and hypoxia-induced regulation of metabolism. This includes activation of innate immunity and complement activation, including activation of cellular inﬂammasome through pattern recognition receptors (TLRs). We wished to elaborate mechanisms that regulate RPE-choroidal microenvironment in AMD. One hypothesis is that, via TLR stimulation, up-regulation of interleukin-33 (IL-33) in retinal pigment epithelial cells (RPE) activates in a ST2 (Il-33 receptor)-dependent manner both choroidal stromal fibroblasts and mast cells. Through such mechanisms, change in choroidal architecture may occur, contributing to the insidious degeneration observed clinically.
RPE cells (ARPE-19 and B6-RPE07) were stimulated with TLR ligands and expression profile and secretion of IL-33 was determined by RT-PCR, Western blots and immunostaining. Function and expression profile of bone-marrow-derived mast cells (BMMC) and human choroidal fibroblasts was also assessed.
IL-33 was highly expressed in the retina of naïve mice, and its receptor ST2 was expressed in RPE, choroidal mast cells and choroidal fibroblasts in mouse and man. Treatment of RPE with TLR ligands (LPS or poly(I:C)) resulted in significant up-regulation of IL-33 expression and secretion, which was enhanced upon TLR-stimulation under hypoxic conditions. ST2+ bone marrow derived mast cells (BMMC) generated a spectrum of inflammatory cytokines and prostaglandin synthase 2 (PGS2) when cultured with IL-33 rich RPE supernatant. Pretreatment with soluble ST2 markedly inhibited the ability of BMMC to produce proinflammatory mediators. Importantly, activation of inflammatory cascade upon RPE supernatant treatment was abrogated in the absence of ST2 in BMMC from ST2-/- mice. Furthermore, recombinant IL-33 treatment of human choroidal fibroblasts impaired their ability to migrate and contract collagen gel, while expression of MMP-2 and -9 was reduced.
Our data illuminate an endogenous IL33/ST2 pathway between RPE function and choroidal stroma, influencing tissue remodeling. Our findings support IL-33/ST2 axis as a therapeutic target in atrophic AMD.
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