Cytosolic phospholipase A2α–deficient mice are resistant to experimental autoimmune encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE), a Th1-mediated inflammatory disease of the central nervous system (CNS), is a model of human multiple sclerosis. Cytosolic phospholipase A2 α (cPLA2 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 cPLA2 α −/− mice are resistant to EAE. Histologic examination of the CNS from MOG-immunized mice revealed extensive inflammatory lesions in the cPLA2 α +/− mice, whereas the lesions in cPLA2 α −/− mice were reduced greatly or completely absent. MOG-specific T cells generated from WT mice induced less severe EAE in cPLA2 α −/− mice compared with cPLA2 α +/− mice, which indicates that cPLA2 α plays a role in the effector phase of EAE. Additionally, MOG-specific T cells from cPLA2 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 cPLA2 α also plays a role in the induction phase of EAE. MOG-specific T cells from cPLA2 α −/− mice were deficient in production of Th1-type cytokines. Consistent with this deficiency, in vivo administration of IL-12 rendered cPLA2 α −/− mice susceptible to EAE. Our data indicate that cPLA2 α plays an important role in EAE development and facilitates differentiation of T cells toward the Th1 phenotype.