Sigma receptor 1 activation attenuates release of inflammatory cytokines MIP1γ, MIP2, MIP3α, and IL12 (p40/p70) by retinal Müller glial cells

Arul Kumaran Shanmugam, Jing Wang, Shanu Markand, Richard L. Perry, Amany Mohamed Tawfik, Eric Zorrilla, Vadivel Ganapathy, Sylvia B Smith

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 (MIP1γ, MIP2, MIP3α) and interleukin-12 (IL12 (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 MIP1γ, MIP2, MIP3α and IL12 (p40/p70) secretion when exposed to LPS compared to LPS-stimulated WT cells. We investigated whether cytokine secretion was accompanied by cytosolic-to-nuclear NFκB translocation and whether endothelial cell adhesion/migration was altered by released cytokines. Cells exposed to LPS demonstrated increased NFκB 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.

Original languageEnglish (US)
Pages (from-to)546-558
Number of pages13
JournalJournal of Neurochemistry
Volume132
Issue number5
DOIs
StatePublished - Mar 1 2015

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Interleukin-12
Neuroglia
Lipopolysaccharides
Chemical activation
Cytokines
Endothelial cells
Cell adhesion
Endothelial Cells
Cells
Ligands
Pentazocine
Macrophage Inflammatory Proteins
Cell Adhesion
Cell Movement
Conditioned Culture Medium
adjuvant P40
sigma-1 receptor
Retinal Diseases
Gliosis
Knockout Mice

Keywords

  • (+)-pentazocine
  • cytokine array
  • mouse
  • radial glial cell
  • retinal degeneration
  • retinal disease

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Sigma receptor 1 activation attenuates release of inflammatory cytokines MIP1γ, MIP2, MIP3α, and IL12 (p40/p70) by retinal Müller glial cells. / Shanmugam, Arul Kumaran; Wang, Jing; Markand, Shanu; Perry, Richard L.; Tawfik, Amany Mohamed; Zorrilla, Eric; Ganapathy, Vadivel; Smith, Sylvia B.

In: Journal of Neurochemistry, Vol. 132, No. 5, 01.03.2015, p. 546-558.

Research output: Contribution to journalArticle

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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 M{\"u}ller cell reactive gliosis, which includes cytokine release. Here, we investigated whether lipopolysaccharide (LPS) stimulates cytokine release by primary mouse M{\"u}ller cells and whether (+)-PTZ alters release. Using a highly sensitive inflammatory antibody array we observed significant release of macrophage inflammatory proteins (MIP1γ, MIP2, MIP3α) and interleukin-12 (IL12 (p40/p70)) in LPS-treated cells compared to controls, and a significant decrease in secretion upon (+)-PTZ treatment. M{\"u}ller cells from σR1 knockout mice demonstrated increased MIP1γ, MIP2, MIP3α and IL12 (p40/p70) secretion when exposed to LPS compared to LPS-stimulated WT cells. We investigated whether cytokine secretion was accompanied by cytosolic-to-nuclear NFκB translocation and whether endothelial cell adhesion/migration was altered by released cytokines. Cells exposed to LPS demonstrated increased NFκB nuclear location, which was reduced significantly in (+)-PTZ-treated cells. Media conditioned by LPS-stimulated-M{\"u}ller 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 M{\"u}ller cells can be attenuated by σR1 ligands providing insights into the retinal neuroprotective role of this receptor.",
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AU - Ganapathy, Vadivel

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