Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent
Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent
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DOI：
10.4049/jimmunol.180.2.1169
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发表时间：
2008-01-15
影响因子：
4.4
通讯作者：
Couillin, Isabelle
中科院分区：
文献类型：
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作者：
Doz, Emilie;Noulin, Nicolas;Couillin, Isabelle
呼吸道的急性香烟烟雾暴露（每天两支香烟，持续三天）诱导小鼠的急性炎症。在这项研究中，我们表明，气道炎症是依赖于Toll样受体4和IL-1 R1信号。香烟烟雾诱导支气管肺泡腔和肺实质中中性粒细胞的显著募集，这在TLR 4-、MyD 88-和IL-1 R1-缺陷小鼠中减少。减少中性粒细胞流入与减少IL-1，IL-6，角质形成细胞衍生的趋化因子水平和基质金属蛋白酶-9活性在支气管肺泡腔。此外，香烟烟雾冷凝物（CSC）在体外诱导巨噬细胞促炎反应，其依赖于MyD 88、IL-1 R1和TLR 4信号传导，但不归因于LPS。热休克蛋白70是一种已知的TLR 4激动剂，在烟雾暴露后在气道中被诱导，这可能通过TLR 4/MyD 88激活先天免疫系统，导致气道炎症。CSC活化的巨噬细胞仅在ATP存在下释放成熟的IL-1 β，而CSC单独促进TLR 4/MyD 88信号传导依赖性的IL-1 α和pro-IL-1 β的产生，暗示TLR和炎性小体之间的合作。总之，急性香烟暴露导致LPS非依赖性TLR 4活化，导致IL-1产生和IL-1 R1信号传导，这对于香烟烟雾诱导的炎症导致慢性阻塞性肺疾病伴肺气肿至关重要。
Acute cigarette smoke exposure of the airways (two cigarettes twice daily for three days) induces acute inflammation in mice. In this study, we show that airway inflammation is dependent on Toll-like receptor 4 and IL-1R1 signaling. Cigarette smoke induced a significant recruitment of neutrophils in the bronchoalveolar space and pulmonary parenchyma, which was reduced in TLR4-, MyD88-, and IL-1R1-deficient mice. Diminished neutrophil influx was associated with reduced IL-1, IL-6, and keratinocyte-derived chemokine levels and matrix metalloproteinase-9 activity in the bronchoalveolar space. Further, cigarette smoke condensate (CSC) induced a macrophage proinflammatory response in vitro, which was dependent on MyD88, IL-1R1, and TLR4 signaling, but not attributable to LPS. Heat shock protein 70, a known TLR4 agonist, was induced in the airways upon smoke exposure, which probably activates the innate immune system via TLR4/MyD88, resulting in airway inflammation. CSC-activated macrophages released mature IL-1 beta only in presence of ATP, whereas CSC alone promoted the TLR4/MyD88 signaling dependent production of IL-1 alpha and pro-IL-1 beta implicating cooperation between TLRs and the inflammasome. In conclusion, acute cigarette exposure results in LPS-independent TLR4 activation, leading to IL-1 production and IL-1R1 signaling, which is crucial for cigarette smoke induced inflammation leading to chronic obstructive pulmonary disease with emphysema.