Sigma receptor 1 activation attenuates release of inflammatory cytokines <scp>MIP</scp>1γ, <scp>MIP</scp>2, <scp>MIP</scp>3α, and <scp>IL</scp>12 (p40/p70) by retinal Müller glial cells

Abstract

Abstract The high‐affinity sigma receptor 1 (σR1) ligand (+)‐pentazocine ((+)‐ PTZ ) affords profound retinal neuroprotection in vitro and in vivo by a yet‐unknown mechanism. A common feature of retinal disease is Müller cell reactive gliosis, which includes cytokine release. Here, we investigated whether lipopolysaccharide ( LPS ) stimulates cytokine release by primary mouse Müller cells and whether (+)‐ PTZ alters release. Using a highly sensitive inflammatory antibody array we observed significant release of macrophage inflammatory proteins ( MIP 1γ, MIP 2, MIP 3α) and interleukin‐12 ( IL 12 (p40/p70)) in LPS ‐treated cells compared to controls, and a significant decrease in secretion upon (+)‐ PTZ treatment. Müller cells from σR1 knockout mice demonstrated increased MIP 1γ, MIP 2, MIP 3α and IL 12 (p40/p70) secretion when exposed to LPS compared to LPS ‐stimulated WT cells. We investigated whether cytokine secretion was accompanied by cytosolic‐to‐nuclear NF κB translocation and whether endothelial cell adhesion/migration was altered by released cytokines. Cells exposed to LPS demonstrated increased NF κB nuclear location, which was reduced significantly in (+)‐ PTZ ‐treated cells. Media conditioned by LPS ‐stimulated‐Müller cells induced leukocyte‐endothelial cell adhesion and endothelial cell migration, which was attenuated by (+)‐ PTZ treatment. The findings suggest that release of certain inflammatory cytokines by Müller cells can be attenuated by σR1 ligands providing insights into the retinal neuroprotective role of this receptor. image A common feature of retinal disease is Müller cell reactive gliosis, which includes cytokine release. To understand how sigma receptor 1 (σR1) mediates neuroprotection, we examined the effects of a high‐affinity σR1 ligand, (+)‐pentazocine, on LPS‐stimulated cytokine release in primary mouse retinal Müller glial cells. Under basal conditions, cytokine release was minimal. LPS stimulation markedly increased secretion of the cytokines MIP1γ, MIP2, MIP3α, IL12 (p40/p70), which was accompanied by a significant translocation of NFκB from cytoplasm to the nucleus. LPS‐treatment in the presence of (+)‐pentazocine markedly decreased cytokine release accompanied by a significant decrease in NFκB localized to the nucleus. IL, interleukin; MIP, macrophage inflammatory proteins.