Nance Stephanie C, Yi Ae-Kyung, Re Fabio C, Fitzpatrick Elizabeth A
Deptartment of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
J Leukoc Biol. 2008 May;83(5):1207-17. doi: 10.1189/jlb.0607391. Epub 2008 Feb 19.
Hypersensitivity pneumonitis is an interstitial lung disease that is characterized by alveolitis, granuloma formation, and in some patients, fibrosis. Using the Saccharopolyspora rectivirgula animal model of Farmer's lung disease, our laboratory has demonstrated that neutrophils play a critical role in IFN-gamma production during the acute phase of the disease. As IFN-gamma is necessary for granuloma formation, it is important to identify the factors that lead to neutrophil recruitment during disease. To begin to identify the pattern recognition receptors (PRRs) that initiate chemokine production, leading to neutrophil recruitment following S. rectivirgula exposure, we examined the role of MyD88 and TLR2. Our results demonstrate that neutrophil recruitment, as measured by flow cytometry and the myeloperoxidase assay, was abolished in the absence of MyD88 following S. rectivirgula exposure. The decrease in neutrophil recruitment was likely a result of a significant decrease in production of neutrophil chemokines MIP-2 and keratinocyte-derived chemokine. These results suggest that S. rectivirgula interacts with PRRs that are upstream of the MyD88 pathway to initiate cytokine and chemokine production. In vitro studies suggest that S. rectivirgula can interact with TLR2, and stimulation of adherent cells from TLR2 knockout (KO) mice with S. rectivirgula resulted in a significant decrease in MIP-2 production. However, TLR2 KO mice did not have a reduction in neutrophil recruitment compared with wild-type mice following S. rectivirgula exposure. The results from our studies suggest that one or more PRR(s) upstream of MyD88 are necessary for neutrophil recruitment following S. rectivirgula exposure.
过敏性肺炎是一种间质性肺病，其特征为肺泡炎、肉芽肿形成，部分患者还会出现肺纤维化。利用农民肺疾病的嗜热放线菌动物模型，我们实验室已证明，中性粒细胞在该疾病急性期的γ干扰素产生过程中起关键作用。由于γ干扰素是肉芽肿形成所必需的，因此确定疾病期间导致中性粒细胞募集的因素很重要。为了开始确定启动趋化因子产生从而导致嗜热放线菌暴露后中性粒细胞募集的模式识别受体（PRR），我们研究了髓样分化因子88（MyD88）和Toll样受体2（TLR2）的作用。我们的结果表明，在嗜热放线菌暴露后，通过流式细胞术和髓过氧化物酶测定法测量，在缺乏MyD88的情况下，中性粒细胞募集被消除。中性粒细胞募集的减少可能是由于中性粒细胞趋化因子巨噬细胞炎性蛋白-2（MIP-2）和角质形成细胞衍生趋化因子产生显著减少所致。这些结果表明，嗜热放线菌与MyD88信号通路上游的PRR相互作用，以启动细胞因子和趋化因子的产生。体外研究表明，嗜热放线菌可与TLR2相互作用，用嗜热放线菌刺激来自TLR2基因敲除（KO）小鼠的贴壁细胞会导致MIP-2产生显著减少。然而，与野生型小鼠相比，嗜热放线菌暴露后，TLR2 KO小鼠的中性粒细胞募集并未减少。我们的研究结果表明，MyD88上游的一种或多种PRR是嗜热放线菌暴露后中性粒细胞募集所必需的。
