Critical role for IL-18 in spontaneous lung inflammation caused by autophagy deficiency.
Critical role for IL-18 in spontaneous lung inflammation caused by autophagy deficiency.
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DOI：
10.4049/jimmunol.1402277
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发表时间：
2015-06-01
期刊：
影响因子：
--
通讯作者：
Eissa NT
中科院分区：
文献类型：
--
作者：
Abdel Fattah E;Bhattacharya A;Herron A;Safdar Z;Eissa NT
自噬是免疫反应的重要组成部分。然而，自噬在人类疾病中的功能却知之甚少。我们研究了在骨髓细胞中缺乏必需的自噬基因Atg7或Atg5的小鼠中自噬缺陷的生物学后果。令人惊讶的是，这些小鼠表现出自发性无菌肺部炎症，其特征在于炎性细胞的显著募集、粘膜下增厚、杯状细胞化生和胶原含量增加。肺部炎症与支气管肺泡灌洗液和血清中几种促炎细胞因子的增加有关。这种炎症主要由白细胞介素18驱动，这是组成性炎性小体激活的结果。腹腔内注射LPS后，自噬缺陷小鼠的肺和血清中促炎细胞因子水平较高，死亡率也高于对照小鼠。鼻内博来霉素激发加重了自噬缺陷小鼠的肺部炎症，并产生了比对照小鼠更严重的纤维化变化。这些结果揭示了自噬作为肺部炎症负调节因子的新的重要作用。
Autophagy is an important component of the immune response. However, the functions of autophagy in human diseases are much less understood. We studied biological consequences of autophagy deficiency in mice lacking the essential autophagy genes Atg7 or Atg5 in myeloid cells. Surprisingly, these mice presented with spontaneous sterile lung inflammation, characterized by marked recruitment of inflammatory cells, submucosal thickening, goblet cell metaplasia and increased collagen content. Lung inflammation was associated with increase in several pro-inflammatory cytokines in the bronchoalveolar lavage and in serum. This inflammation was largely driven by interleukin 18 as a result of constitutive inflammasome activation. Following intraperitoneal LPS injection, autophagy deficient mice had higher levels of pro-inflammatory cytokines in lungs and in serum, as well as increased mortality than control mice. Intranasal bleomycin challenge exacerbated lung inflammation in autophagy deficient mice and produced more severe fibrotic changes than in control mice. These results uncover a new and important role for autophagy as negative regulator of lung inflammation.
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DOI：
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发表时间：
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