title: The role of lipoprotein-associated phospholipase A2 in a murine model of experimental autoimmune uveoretinitis.
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.
authors: Academic unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors: G L
authors: GL
authors: Crawford
authors: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors: J
authors: J
authors: Boldison
authors: Academic unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors: D A
authors: DA
authors: Copland
authors: Ophthiris Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom.
authors: P
authors: P
authors: Adamson
authors: Ophthiris Discovery Performance Unit, GlaxoSmithKline, King of Prussia, Pennsylvania, United States of America.
authors: D
authors: D
authors: Gale
authors: Platform Technology Sciences, King of Prussia, Pennsylvania, United States of America.
authors: M
authors: M
authors: Brandt
authors: Academic unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors: L B
authors: LB
authors: Nicholson
authors: Academic unit of Ophthalmology, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors: A D
authors: AD
authors: Dick
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression / Q000235:genetics; D007114:Immunization; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010455:Peptides / Q000276:immunology; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology; D012173:Retinitis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014605:Uveitis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D001713:Biphenyl Compounds; D008070:Lipopolysaccharides; D010455:Peptides; D011744:Pyrimidinones; C470971:SB-435495; D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C571209:Pla2g7 protein, mouse