Toll-Like Receptor 2 Regulates Organic Dust-Induced Airway Inflammation
Toll-Like Receptor 2 Regulates Organic Dust-Induced Airway Inflammation
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DOI：
10.1165/rcmb.2010-0427oc
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发表时间：
2011-10-01
影响因子：
6.4
通讯作者：
Romberger, Debra J.
中科院分区：
文献类型：
--
作者：
Poole, Jill A.;Wyatt, Todd A.;Romberger, Debra J.
农业环境中有机粉尘暴露会导致严重的呼吸道炎症性疾病。在动物养殖粉尘中存在高浓度的革兰氏阳性细胞壁成分，但它们在介导粉尘诱导的呼吸道炎症中的作用尚不清楚。本研究探讨了革兰氏阳性细胞壁产物的模式识别受体Toll样受体(TLR)2在调节猪设施有机粉尘提取物(DE)诱导的小鼠呼吸道炎症中的作用。体外培养的TLR2基因敲除小鼠肺巨噬细胞经DE刺激后，肿瘤坏死因子-α、IL-6、角质形成细胞趋化因子/CXCL1表达降低，但巨噬细胞炎性蛋白-2/CXCL2表达无明显变化。接下来，使用建立的小鼠鼻内吸入攻击模型，我们分析了TLR2缺陷和野生型(WT)小鼠在单一和重复DE攻击后的支气管肺泡灌洗液和肺组织。在单一DE攻击后5小时和24小时，TLR2基因缺陷小鼠的中性粒细胞内流和选择性细胞因子/趋化因子显著降低。每天暴露于DE 2周后，与WT组相比，TLR2基因缺陷小鼠的细胞总数、中性粒细胞内流和肿瘤坏死因子-α、IL-6、CXCL1的表达显著降低，而CXCL2的表达无明显变化。肺部病理显示，反复暴露后，TLR2基因缺陷小鼠的细支气管炎有所减轻，但肺泡炎并未减轻。粉尘暴露后，两组患者对乙酰甲胆碱的高反应性相似。最后，WT小鼠在用TLR2激动剂肽聚糖攻击后的呼吸道炎症反应类似于DE诱导的反应。综上所述，这些结果表明TLR2通路在调节猪设施有机粉尘诱导的呼吸道炎症中起重要作用，这表明TLR2激动剂在介导大型动物饲养诱导的呼吸道炎症反应中的重要性。
Organic dust exposure in agricultural environments results in significant airway inflammatory diseases. Gram-positive cell wall components are present in high concentrations in animal farming dusts, but their role in mediating dust-induced airway inflammation is not clear. This study investigated the role of Toll-like receptor (TLR) 2, a pattern recognition receptor for gram-positive cell wall products, in regulating swine facility organic dust extract (DE)-induced airway inflammation in mice. Isolated lung macrophages from TLR2 knockout mice demonstrated reduced TNF-alpha, IL-6, keratinocyte chemoattractant/CXCL1, but not macrophage inflammatory protein-2/CXCL2 expression, after DE stimulation ex vivo. Next, using an established mouse model of intranasal inhalation challenge, we analyzed bronchoalveolar lavage fluid and lung tissue in TLR2-deficient and wild-type (WT) mice after single and repetitive DE challenge. Neutrophil influx and select cytokines/chemokines were significantly lower in TLR2-deficient mice at 5 and 24 hours after single DE challenge. After daily exposure to DE for 2 weeks, there were significant reductions in total cellularity, neutrophil influx, and TNF-alpha, IL-6, CXCL1, but not CXCL2 expression, in TLR2-deficient mice as compared with WT animals. Lung pathology revealed that bronchiolar inflammation, but not alveolar inflammation, was reduced in TLR2-deficient mice after repetitive exposure. Airway hyperresponsiveness to methacholine after dust exposure was similar in both groups. Finally, airway inflammatory responses in WT mice after challenge with a TLR2 agonist, peptidoglycan, resembled DE-induced responses. Collectively, these results demonstrate that the TLR2 pathway is important in regulating swine facility organic dust-induced airway inflammation, which suggests the importance of TLR2 agonists in mediating large animal farming-induced airway inflammatory responses.