Cytosolic phospholipase A2 plays a key role in the pathogenesis of multiple sclerosis-like disease

Neuron. 2004 Feb 5;41(3):323-35. doi: 10.1016/s0896-6273(04)00003-0.

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that results in motor and sensory deficits. Although MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are thought to be T cell-mediated diseases, the mechanisms underlying the lesions in the CNS are not fully understood. We propose that a strong candidate as a central mediator in evoking the complex pathological changes seen in MS and EAE is the enzyme cytosolic phospholipase A2 (cPLA2). One of the metabolic products of this enzyme is pro-inflammatory, while the other induces myelin breakdown, demyelination, and chemokine/cytokine expression. We provide evidence that cPLA2 is highly expressed in EAE lesions and show that blocking this enzyme leads to a remarkable reduction in the onset and progression of EAE.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / therapeutic use
  • Axons / enzymology
  • Axons / pathology
  • Axons / ultrastructure
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / enzymology
  • Cell Count
  • Chemokines / genetics
  • Chemokines / metabolism
  • Cyclooxygenase 2
  • Cytokinins / genetics
  • Cytokinins / metabolism
  • Cytosol / enzymology
  • Disease Models, Animal
  • Endothelial Cells / enzymology
  • Endothelial Cells / pathology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Gene Expression / drug effects
  • Immunohistochemistry / methods
  • Inflammation / chemically induced
  • Inflammation / pathology
  • Isoenzymes / metabolism
  • Macrophages / enzymology
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron
  • Multiple Sclerosis / chemically induced
  • Multiple Sclerosis / enzymology*
  • Multiple Sclerosis / pathology
  • Multiple Sclerosis / prevention & control
  • Oligonucleotide Array Sequence Analysis / methods
  • Phospholipases A / metabolism*
  • Phospholipases A2
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • RNA, Messenger / biosynthesis
  • Random Allocation
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Spinal Cord / cytology
  • Spinal Cord / enzymology
  • Spinal Cord / pathology
  • Time Factors

Substances

  • Arachidonic Acids
  • Chemokines
  • Cytokinins
  • Enzyme Inhibitors
  • Isoenzymes
  • RNA, Messenger
  • Receptors, Chemokine
  • arachidonyltrifluoromethane
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Phospholipases A
  • Phospholipases A2