Abstract
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.
Highlights
Non-anterior uveitis is a collective term used to describe a range of intraocular inflammatory disorders affecting the uvea and retina, and whilst more rare than anterior uveitis, is significantly more sight threatening [1]
To determine basal enzyme activity status of the Lipoprotein-Associated phospholipase A2 (Lp-phospholipase A2 (PLA2)) KO, HET and WT mice, cardiac blood samples were processed for plasma analysis, which confirmed that Lp-PLA2 activity was highest in WT animals, reduced in HETs and absent in Lp-PLA2 KO mice (Fig 1A)
We have successfully shown that SB-435495 is an effective, reversible inhibitor of Lp-PLA2 both in bone marrow derived macrophages (BMDM) in vitro and in an in vivo murine model of experimental autoimmune uveoretinitis (EAU)
Summary
Non-anterior uveitis (posterior, pan and intermediate uveitis) is a collective term used to describe a range of intraocular inflammatory disorders affecting the uvea and retina, and whilst more rare than anterior uveitis, is significantly more sight threatening [1]. Experimental autoimmune uveoretinitis (EAU) is an antigen-specific Th1/Th17 CD4+ T cell-directed murine model, employed to mimic human non-infectious, non-anterior uveitis, which has been utilised extensively to develop a detailed understanding of the immuno-pathogenesis of vascular inflammation, retinal leukocyte infiltration and mechanisms of tissue damage [6,7,8]. In this model, tissue destruction is dependent upon activation and infiltration of mononuclear cell infiltration [6, 9,10,11,12]. Notwithstanding, regulating macrophage activation will reduce inflammation [17, 18] and as such, an ability to manipulate macrophage phenotype and/or migration has the potential to abrogate EAU onset
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