Abstract

Muller cells play a prominent role in inflammatory conditions of the retina. They are part of the retinal innate immune response. The endocannabinoid system functions as an immune modulator in both the peripheral immune system as well as the central nervous system. We hypothesized that the neuroprotective ability of exogenous endocannabinoids in the retina is partially mediated through Muller glia. This study reports that exposure to endocannabinoids in activated but not resting primary human Muller glia inhibit production of several proinflammatory cytokines, while elevating anti-inflammatory mediators. Cytokine generation in activated Muller glia is regulated by endocannabinoids through the mitogen-activated protein kinase (MAPK) family at multiple signaling stages. Anandamide (AEA) acts to control MAPK phosphorylation through MKP-1. Both AEA and 2-arachidonoylglycerol (2-AG) inhibit the transcription factor NF-κB and increases the regulatory protein, IL1-R-associated kinase 1-binding protein 1. Endocannabinoids also increase expression of Tristetraprolin in activated Muller cells, which is implicated in affecting AU-rich proinflammatory cytokine mRNA. We demonstrate that exogenous application of AEA and 2-AG aid in retinal cell survival under inflammatory conditions by creating an anti-inflammatory milieu. Endocannabinoids or synthetic cannabinoid therapy may therefore orchestrate a molecular switch to bias the innate immune system suchthat the balance of pro- and anti-inflammatory cytokine generation creates a prosurvival milieu.

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Publisher Full Text

Authors

Krishnan G, Chatterjee N

Institution

Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, 41 College Road, Chennai 600006, India.

Source

Glia 60:11 2012 Nov pg 1629-45

MeSH

Adult
Aged
Aged, 80 and over
Arachidonic Acids
Cannabinoid Receptor Agonists
Cells, Cultured
Cytokines
Endocannabinoids
Glycerides
Humans
Immunity, Innate
Inflammation
Middle Aged
Mitogen-Activated Protein Kinases
Neuroglia
Phosphorylation
Polyunsaturated Alkamides
Retina
Tristetraprolin

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22807196