Radical-Containing Particles Activate Dendritic Cells and Enhance Th17 Inflammation in a Mouse Model of Asthma
Radical-Containing Particles Activate Dendritic Cells and Enhance Th17 Inflammation in a Mouse Model of Asthma
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DOI：
10.1165/rcmb.2011-0001oc
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发表时间：
2011-11-01
影响因子：
6.4
通讯作者：
Cormier, Stephania A.
中科院分区：
文献类型：
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作者：
Wang, Pingli;Thevenot, Paul;Cormier, Stephania A.
我们确定了燃烧和热过程中形成的空气颗粒物(PM)中一种以前未被识别的成分，即环境持久性自由基(EPFR)。EPFR对肺部健康的影响目前尚不清楚。在目前的研究中，我们使用了一个包含EPFR的污染物-颗粒系统模型，称为MCP230。我们评价了MCP230对体外培养的骨髓来源的树突状细胞(BMDCs)和体内的肺树突状细胞(DCs)的表型和功能的影响，以及随后的T细胞应答。我们还研究了MCP230在哮喘小鼠模型中对呼吸道炎症的佐剂作用。MCP230降低BMDCs内还原型谷胱甘肽(GSH)和GSH/氧化谷胱甘肽的比值，上调DC表面共刺激分子CD80和CD86的表达。通过抑制氧化应激或MCP230的摄取来阻止DC的成熟。BMDCs暴露于MCP230后，体外可促进其抗原特异性T细胞的增殖。在哮喘模型中，暴露于MCP230加剧了肺部炎症，这归因于中性粒细胞和巨噬细胞的增加，而不是嗜酸性粒细胞的增加。这一结果与Th17细胞和细胞因子的增加有关，与未经MCP230治疗但卵蛋白(OVA)攻击的小鼠相比。OVA和OVA 1MCP230小鼠的Th2细胞百分率相近。我们的数据表明，燃烧产生的、含有EPFR的PM以摄取依赖和氧化应激依赖的方式直接诱导DC成熟。此外，含有EPFR的PM在肺中诱导了偏向Th17的表型，并伴有明显的肺中性粒细胞减少。暴露于含有EPFR的PM可能是人类严重哮喘表型恶化和发展的一个重要且未被认识到的危险因素。
We identified a previously unrecognized component of airborne particulate matter (PM) formed in combustion and thermal processes, namely, environmentally persistent free radicals (EPFRs). The pulmonary health effects of EPFRs are currently unknown. In the present study, we used a model EPFR-containing pollutant-particle system referred to as MCP230. We evaluated the effects of MCP230 on the phenotype and function of bone marrow-derived dendritic cells (BMDCs) in vitro and lung dendritic cells (DCs) in vivo, and the subsequent T-cell response. We also investigated the adjuvant role of MCP230 on airway inflammation in a mouse model of asthma. MCP230 decreased intracellular reduced glutathione (GSH) and the GSH/oxidized glutathione ratio in BMDCs, and up-regulated the expression of costimulatory molecules CD80 and CD86 on DCs. The maturation of DCs was blocked by inhibiting oxidative stress or the uptake of MCP230. BMDCs exposed to MCP230 increased their antigen-specific T-cell proliferation in vitro. In a model of asthma, exposure to MCP230 exacerbated pulmonary inflammation, which was attributed to the increase of neutrophils and macrophages but not eosinophils. This result correlated with an increase in Th17 cells and cytokines, compared with non-MCP230-treated but ovalbumin (OVA)-challenged mice. The percentage of Th2 cells was comparable between OVA and OVA 1 MCP230 mice. Our data demonstrate that combustion-generated, EPFR-containing PM directly induced the maturation of DCs in an uptake-dependent and oxidative stress-dependent manner. Furthermore, EPFR-containing PM induced a Th17-biased phenotype in lung, accompanied by significant pulmonary neutrophilia. Exposure to EPFR-containing PM may constitute an important and unrecognized risk factor in the exacerbation and development of a severe asthma phenotype in humans.