The role of Lipoprotein-Associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis

Macrophage activation is, in part, regulated via hydrolysis of oxidised low density lipoproteins by Lipoprotein-Associated phospholipase A₂ (Lp-PLA₂), resulting in increased macrophage migration, pro-inflammatory cytokine release and chemokine expression. In uveitis, tissue damage is mediated as a result of macrophage activation; hence inhibition of Lp-PLA₂ may limit macrophage activation and protect the tissue. Utilising Lp-PLA₂ gene-deficient (KO) mice and a pharmacological inhibitor of Lp-PLA₂ (SB-435495) we aimed to determine the effect of Lp-PLA₂ suppression in mediating retinal protection in a model of autoimmune retinal inflammation, experimental autoimmune uveoretinitis (EAU). Following immunisation with RBP-3 (IRBP) 1-20 or 161-180 peptides, clinical disease was monitored and severity assessed, infiltrating leukocytes were enumerated by flow cytometry and tissue destruction quantified by histology. Despite ablation of Lp-PLA₂ enzyme activity in Lp-PLA₂ KO mice or wild-type mice treated with SB-435495, the number of infiltrating CD45⁺ cells in the retina was equivalent to control EAU animals, and there was no reduction in disease severity. Thus, despite the reported beneficial effects of therapeutic Lp-PLA₂ depletion in a variety of vascular inflammatory conditions, we were unable to attenuate disease, show delayed disease onset or prevent progression of EAU in Lp-PLA₂ KO mice. Although EAU exhibits inflammatory vasculopathy there is no overt defect in lipid metabolism and given the lack of effect following Lp-PLA₂ suppression, these data support the hypothesis that sub-acute autoimmune inflammatory disease progresses independently of Lp-PLA₂ activity.