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Arul Shanmugam, Shanu Markand, Amany M Tawfik, Eric Zorrilla, Vadivel Ganapathy, Sylvia B Smith; Influence of sigma receptor-1 (σR1) on inflammatory, stress and toxicity mediators in retinal Müller glia (rMG). Invest. Ophthalmol. Vis. Sci. 2014;55(13):6325.
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© ARVO (1962-2015); The Authors (2016-present)
σR1 is a transmembrane protein expressed in many tissues including retina. Studies from our lab & others demonstrated profound neuroprotective properties of ligands for σR1 in vitro & in vivo. Studies of mechanisms of σR1-mediated neuroprotection have focused mainly on neurons, especially ganglion cells. The role of σR1 in rMG has not been investigated. Given the crucial role of these cells in maintaining retinal structure/function, we used targeted arrays to examine involvement of σR1 in modulating inflammatory & stress/toxicity mediators in rMG.
Primary Müller cells (1°MC) were isolated from 5-7 day C57BL/6J σR1+/+ (WT) pups, passaged 3-5X, incubated with LPS (0.1μg/ml, 24 h) in the presence/absence of (+)-pentazocine ((+)-PTZ), a σR1 ligand. Secretion of 62 cytokines was assessed using the RayBio inflammatory array kit. We then studied the influence of σR1 on gene expression in 1°MC isolated from WT & σR1 -/- (KO) pups; cDNA was subjected to the BioRad Stress/Toxicity PCR array, which allowed analysis of 90 genes.
Exposure of WT 1°MC to LPS induced secretion of numerous inflammatory cytokines: IL-6, IL-12P40/P70, MCP-1, CTACK, RANTES (>20-fold); CXCL16, GCSF, KC (>10-fold); IL-3, IL-5, leptin R, MIP-1γ, MIP-2, MIP-3α, SDF-1α, sTNFR1 (>3-fold); & a 2-fold decrease in IGFBP-3, IGFBP-5 compared to untreated cells. Pre/co-treatment with (+)-PTZ yielded a substantial decrease in LPS-induced cytokines: CTACK, IL-3, IL-12P40/P70, leptin R, MIP-1γ, MIP-2, MIP-3α & an increase in IGFBP-3 and 5, compared with LPS treatment alone. Examination of stress/toxicity genes in WT versus KO 1°MC revealed a ~50 fold increase in CCL-12, Cftr, endothelin 1, Grb-2, Hbb-b1, a ~38-fold increase in aquaporin-4, & a ~3-fold increase in Arnt, Atf4, Atf6b, Gadd-45a, Gsr, in KO 1°MC compared to WT.
The current experiments address for the first time whether retinal neuroprotective properties of σR1 ligands may act upon rMG as well as neurons. The data suggest that σR1 may play a vital role in attenuating rMG dysfunction induced by inflammatory and stress mediators and may prove promising in a wide range of retinal diseases.
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