Cytosolic phospholipase A(2)α–deficient mice are resistant to experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE), a Th1-mediated inflammatory disease of the central nervous system (CNS), is a model of human multiple sclerosis. Cytosolic phospholipase A(2) α (cPLA(2) α), which initiates production of prostaglandins, leukotrienes, and platelet-activating factor, is present in EAE lesions. Using myelin oligodendrocyte glycoprotein (MOG) immunization, as well as an adoptive transfer model, we showed that cPLA(2) α (−/−) mice are resistant to EAE. Histologic examination of the CNS from MOG-immunized mice revealed extensive inflammatory lesions in the cPLA(2) α (+/−) mice, whereas the lesions in cPLA(2) α (−/−) mice were reduced greatly or completely absent. MOG-specific T cells generated from WT mice induced less severe EAE in cPLA(2) α (−/−) mice compared with cPLA(2) α (+/−) mice, which indicates that cPLA(2) α plays a role in the effector phase of EAE. Additionally, MOG-specific T cells from cPLA(2) α (−/−) mice, transferred into WT mice, induced EAE with delayed onset and lower severity compared with EAE that was induced by control cells; this indicates that cPLA(2) α also plays a role in the induction phase of EAE. MOG-specific T cells from cPLA(2) α (−/−) mice were deficient in production of Th1-type cytokines. Consistent with this deficiency, in vivo administration of IL-12 rendered cPLA(2) α (−/−) mice susceptible to EAE. Our data indicate that cPLA(2) α plays an important role in EAE development and facilitates differentiation of T cells toward the Th1 phenotype.