1. Differing roles for members of the phospholipase A2 superfamily in experimental autoimmune encephalomyelitis
- Author
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Kalyvas, Athena, Baskakis, Constantinos, Magrioti, Victoria, Constantinou-Kokotou, Violetta, Stephens, Daren, López-Vales, Rubèn, Lu, Jian-Qiang, Yong, V Wee, Dennis, Edward A, Kokotos, George, and David, Samuel
- Subjects
Multiple Sclerosis ,Neurosciences ,Autoimmune Disease ,Brain Disorders ,Neurodegenerative ,Inflammatory and immune system ,Adult ,Amides ,Animals ,Cytokines ,Disease Progression ,Encephalomyelitis ,Autoimmune ,Experimental ,Enzyme Inhibitors ,Fatty Acids ,Female ,Flow Cytometry ,Fluorescent Antibody Technique ,Fluorocarbons ,Gene Expression ,Humans ,Immunohistochemistry ,Ketones ,Macrophages ,Male ,Mice ,Mice ,Inbred C57BL ,Phospholipase A2 Inhibitors ,Phospholipases A2 ,Protein Isoforms ,RNA ,Messenger ,Spinal Cord ,T-Lymphocytes ,Young Adult ,EAE ,multiple sclerosis ,Phospholipase A(2) ,fatty acids ,chemokines ,cytokines ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
The phospholipase A(2) (PLA(2)) superfamily hydrolyzes phospholipids to release free fatty acids and lysophospholipids, some of which can mediate inflammation and demyelination, hallmarks of the CNS autoimmune disease multiple sclerosis. The expression of two of the intracellular PLA(2)s (cPLA(2) GIVA and iPLA(2) GVIA) and two of the secreted PLA(2)s (sPLA(2) GIIA and sPLA(2) GV) are increased in different stages of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We show using small molecule inhibitors, that cPLA(2) GIVA plays a role in the onset, and iPLA(2) GVIA in the onset and progression of EAE. We also show a potential role for sPLA(2) in the later remission phase. These studies demonstrate that selective inhibition of iPLA(2) can ameliorate disease progression when treatment is started before or after the onset of symptoms. The effects of these inhibitors on lesion burden, chemokine and cytokine expression as well as on the lipid profile provide insights into their potential modes of action. iPLA(2) is also expressed by macrophages and other immune cells in multiple sclerosis lesions. Our results therefore suggest that iPLA(2) might be an excellent target to block for the treatment of CNS autoimmune diseases, such as multiple sclerosis.
- Published
- 2009