Crawford G L, Boldison J, Copland D A, Adamson P, Gale D, Brandt M, Nicholson L B, Dick A D
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.
PLoS One. 2015 Apr 15;10(4):e0122093. doi: 10.1371/journal.pone.0122093. eCollection 2015.
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.
巨噬细胞的激活部分是通过脂蛋白相关磷脂酶A2（Lp-PLA2）对氧化型低密度脂蛋白的水解来调节的，这会导致巨噬细胞迁移增加、促炎细胞因子释放和趋化因子表达。在葡萄膜炎中，组织损伤是由巨噬细胞激活介导的；因此，抑制Lp-PLA2可能会限制巨噬细胞激活并保护组织。我们利用Lp-PLA2基因缺陷（KO）小鼠和Lp-PLA2的药理学抑制剂（SB-435495），旨在确定在自身免疫性视网膜炎症模型——实验性自身免疫性葡萄膜视网膜炎（EAU）中，Lp-PLA2抑制在介导视网膜保护中的作用。在用视网膜结合蛋白3（IRBP）1-20或161-180肽免疫后，监测临床疾病并评估严重程度，通过流式细胞术计数浸润的白细胞，并通过组织学对组织破坏进行定量。尽管Lp-PLA2 KO小鼠或用SB-435495处理的野生型小鼠中Lp-PLA2酶活性被消除，但视网膜中浸润的CD45+细胞数量与对照EAU动物相当，疾病严重程度也没有降低。因此，尽管在各种血管炎性疾病中报道了治疗性Lp-PLA2消耗的有益效果，但我们无法减轻Lp-PLA2 KO小鼠的疾病、延迟疾病发作或预防EAU的进展。尽管EAU表现出炎症性血管病变，但脂质代谢没有明显缺陷，鉴于Lp-PLA2抑制后没有效果，这些数据支持以下假设：亚急性自身免疫性炎症疾病的进展独立于Lp-PLA2活性。
