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Phospholipase C‐epsilon Mediates Inflammatory Responses in Experimental Autoimmune Encephalomyelitis Progression through its Role in Astrocyte GPCR Signaling
Author(s) -
Purcell Nicole H,
Dusaban Stephanie,
Ryu Jae K,
Akassoglou Katerina,
Smrcka Alan V,
Brown Joan Heller
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1190.6
Subject(s) - astrocyte , experimental autoimmune encephalomyelitis , inflammation , receptor , g protein coupled receptor , knockout mouse , biology , immunology , signal transduction , lipid signaling , multiple sclerosis , gene knockdown , microbiology and biotechnology , central nervous system , neuroscience , cell culture , biochemistry , genetics
Phospholipase C‐epsilon (PLCɛ) is a novel signaling molecule that integrates upstream G‐protein coupled receptor (GPCR) activation to downstream biological processes. We previously demonstrated that PLCɛ is important in mediating inflammatory gene expression in astrocytes in response to GPCR ligands that are released at sites of Central Nervous System (CNS) injury. Multiple Sclerosis (MS) is a CNS disease characterized by inflammation, breakdown of the blood brain barrier (BBB), demyelination, and axonal damage. Because astrocytes play a role in MS progression, and since PLCɛ is important for astrocytic inflammatory responses, we sought to identify the role of PLCɛ in the Experimental Autoimmune Encephalomyelitis (EAE) animal model of MS. Loss of PLCɛ resulted in attenuated clinical scores from days 17 to 30 after EAE induction compared to wild‐type (WT) mice. Spinal cords from knockout (KO) mice also show attenuated iNOS and IL‐1β expression as well as decreased inflammation as assessed by hematoxylin/eosin staining. We also observe S1P 3 receptor and sphingosine kinase‐1 (Sphk1) up‐regulation in spinal cords of WT mice after EAE induction. Further studies demonstrate S1P 3 and Sphk1 mediate inflammatory gene expression in astrocytes. Use of GFAP‐Cre to knock out PLCɛ specifically in astrocytes also demonstrate the role of PLCɛ is primarily through astrocytes. Lastly, GPCR profiling and receptor knockdown including several orphan receptors implicate an importance of receptor coupling to PLCɛ in astrocyte inflammation. Thus, the data presented here demonstrate the importance of PLCɛ in mediating neuroinflammatory responses, which ultimately affects MS progression.