Differing roles for members of the phospholipase A2 superfamily in experimental autoimmune encephalomyelitis

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.

Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter

“…To further determine the role of 5-LOX or 12-LOX in the pathogenesis of EAE, we treated EAE mice with AA861, the LOX inhibitor, AACOCF3, the cPLA 2 inhibitor, and the combination of both from day 7 postimmunization. Consistent with the reports by others (Kalyvas et al, 2009;Kalyvas and David, 2004;Marusic et al, 2005Marusic et al, , 2008, AACOCF3 was found to significantly attenuate the clinical signs of EAE (Fig. 1A).…”

“…Several studies have previously reported that PLA 2 inhibition can diminish the Th1 and Th17 response and the production of inflammatory cytokines and chemokines (Bettelli et al, 2007;Kalyvas and David, 2004;Marusic et al, 2008), however, the role of PLA 2 on the function of the infiltrating macrophage and the activated microglia in EAE are largely unknown. Similar to the findings by others (Kalyvas et al, 2009;Kalyvas and David, 2004), we found that the expression of cPLA 2 is elevated in macrophage and microglia in the EAE mouse spinal cord white matter. Although cPLA 2 is also expressed in neurons and OLs, the differences of its expression in these cell types were not found between the EAE and control animals.…”

“…Inhibition of PLA 2 has been shown to be effective for the treatment of EAE (Kalyvas et al, 2009;Kalyvas and David, 2004;Marusic et al, 2005Marusic et al, , 2008. However, the protective mechanisms of the pharmacological PLA 2 inhibitors are still unclear.…”

“…Recently, it has been shown that the inhibitors of cPLA 2 , iPLA 2 and sPLA 2 can all reduce the severity of EAE, and activation of different PLA 2 isoforms may be involved in the different stages of the disease (Kalyvas et al, 2009). However, except for cPLA 2 α, the role of iPLA 2 and sPLA 2 in the development of EAE has not been validated by using genetic approaches.…”

Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s Act on Distinct Phospholipid Pools in Zymosan-Stimulated Mouse Peritoneal Macrophages

“…(8)(9)(10)(11), the cellular role of iPLA 2 b has not been clearly defined. Initially described as a homeostatic enzyme involved in phospholipid fatty acid remodeling (58)(59)(60), more recent data suggested that the enzyme also plays multiple roles in activated cells, highlighting its potential as a therapeutic candidate for a number of pathophysiological conditions (24)(25)(26)(27)61). In this work, we aimed at both defining and differentiating the contribution of these two PLA 2 s to zymosan-stimulated phospholipid turnover in macrophages.…”