INSERM, U774, Lille, F-59019, France; Institut Pasteur de Lille, Lille, F-59019, France; Univ Lille II, Lille, F-59000 France.
Part Fibre Toxicol. 2009 Mar 13;6:9. doi: 10.1186/1743-8977-6-9.
The exposure to pollutants such as diesel exhaust particles (DEP) is associated with an increased incidence of respiratory diseases. However, the mechanisms by which DEP have an effect on human health are not completely understood. In addition to their action on macrophages and airway epithelial cells, DEP also modulate the functions of dendritic cells (DC). These professional antigen-presenting cells are able to discriminate unmodified self from non-self thanks to pattern recognition receptors such as the Toll like Receptors (TLR) and Scavenger Receptors (SR). SR were originally identified by their ability to bind and internalize modified lipoproteins and microorganisms but also particles and TLR agonists. In this study, we assessed the implication of SR in the effects of DEP associated or not with TLR agonists on monocyte-derived DC (MDDC). For this, we studied the regulation of CD36, CXCL16, LOX-1, SR-A1 and SR-B1 expression on MDDC treated with DEP associated or not with TLR2, 3 and 4 ligands. Then, the capacity of SR ligands (dextran sulfate and maleylated-ovalbumin) to block the effects of DEP on the function of lipopolysaccharide (LPS)-activated DC has been evaluated.
Our data demonstrate that TLR2 agonists mainly augmented CXCL16, LOX-1 and SR-B1 expression whereas DEP alone had only a weak effect. Interestingly, DEP modulated the action of TLR2 and TLR4 ligands on the expression of LOX-1 and SR-B1. Pretreatment with the SR ligand maleylated-ovalbumin but not dextran sulfate inhibited the endocytosis of DEP by MDDC. Moreover, this SR ligand blocked the effect by DEP at low dose (1 mug/ml) on MDDC phenotype (a decrease of CD86 and HLA-DR expression) and on the secretion of CXCL10, IL-12 and TNF-alpha. In contrast, the decrease of IL-12 and CXCL10 secretion and the generation of oxygen metabolite induced by DEP at 10 mug/ml was not affected by SR ligands
Our results show for the first time that the modulation of DC functions by DEP implicates SR. TLR agonists upregulated SR expression in contrast to DEP. Interfering with the expression and/or the function of SR might be one way to limit the impact of DEP on lung immune response.
暴露于污染物，如柴油废气颗粒（DEP），与呼吸道疾病的发病率增加有关。然而，DEP 对人体健康影响的机制尚不完全清楚。除了对巨噬细胞和气道上皮细胞的作用外，DEP 还调节树突状细胞（DC）的功能。这些专业的抗原呈递细胞能够通过模式识别受体（如 Toll 样受体（TLR）和清道夫受体（SR））区分未修饰的自身和非自身。SR 最初是通过其结合和内化修饰的脂蛋白和微生物的能力来识别的，但也可以识别颗粒和 TLR 激动剂。在这项研究中，我们评估了 SR 对与 TLR 激动剂相关或不相关的 DEP 对单核细胞衍生的树突状细胞（MDDC）的影响的意义。为此，我们研究了 DEP 与 TLR2、3 和 4 配体相关或不相关时对 MDDC 中 CD36、CXCL16、LOX-1、SR-A1 和 SR-B1 表达的调节。然后，评估了 SR 配体（葡聚糖硫酸盐和马来酰化卵清蛋白）阻断 DEP 对脂多糖（LPS）激活的 DC 功能的影响。
我们的数据表明，TLR2 激动剂主要增强了 CXCL16、LOX-1 和 SR-B1 的表达，而 DEP 本身的作用较弱。有趣的是，DEP 调节了 TLR2 和 TLR4 配体对 LOX-1 和 SR-B1 表达的作用。用 SR 配体马来酰化卵清蛋白预处理而不是葡聚糖硫酸盐抑制了 MDDC 对 DEP 的内吞作用。此外，这种 SR 配体阻断了 DEP 在低剂量（1μg/ml）下对 MDDC 表型（CD86 和 HLA-DR 表达降低）和 CXCL10、IL-12 和 TNF-α分泌的影响。相反，DEP 在 10μg/ml 时诱导的 IL-12 和 CXCL10 分泌减少和氧代谢物生成不受 SR 配体影响。
我们的结果首次表明，DEP 对 DC 功能的调节涉及到 SR。TLR 激动剂上调了 SR 的表达，而 DEP 则没有。干扰 SR 的表达和/或功能可能是限制 DEP 对肺部免疫反应影响的一种方法。
