IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia.
IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia.
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DOI：
10.1038/mi.2016.107
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发表时间：
2017-07
影响因子：
8
通讯作者：
Standiford TJ
中科院分区：
文献类型：
--
作者：
Aoyagi T;Newstead MW;Zeng X;Kunkel SL;Kaku M;Standiford TJ
流感病毒引起人类呼吸道疾病，可发展为肺损伤，导致致命后果。白细胞介素（IL）-36细胞因子是新近描述的IL-1家族细胞因子，其通过与IL-36受体（IL-36 R）结合来促进炎症反应。IL-36细胞因子的表达机制和作用知之甚少。在这里，我们研究了IL-36细胞因子在调节小鼠流感病毒诱导的肺炎期间的先天性炎症反应中的作用。鼻内给予流感病毒可上调肺中IL-36α mRNA和蛋白质的产生。在体外，流感病毒介导的IL-36α而不是IL-36γ通过caspase-1和caspase-3/7依赖性途径从肺泡上皮细胞（AEC）诱导和分泌。在AEC脱落的微粒中检测到IL-36α，并促进呼吸细胞中促炎细胞因子和趋化因子的产生。IL-36 R缺陷型小鼠免受流感病毒诱导的肺损伤和死亡。死亡率降低与中性粒细胞和单核细胞/巨噬细胞的早期积累、淋巴细胞活化、促炎细胞因子和趋化因子的产生以及肺泡上皮屏障的通透性显著降低相关，尽管病毒清除受损。总之，这些数据表明IL-36配体在流感病毒感染期间加重肺损伤。
Influenza virus causes a respiratory disease in human that can progress to lung injury with fatal outcome. The interleukin (IL)-36 cytokines are newly described IL-1 family cytokines that promote inflammatory responses via binding to the IL-36 receptor (IL-36R). The mechanism of expression and the role of IL-36 cytokines is poorly understood. Here, we investigated the role of IL-36 cytokines in modulating the innate inflammatory response during influenza virus-induced pneumonia in mice. The intranasal administration of influenza virus upregulated IL-36α mRNA and protein production in the lungs. In vitro, influenza virus-mediated IL-36α but not IL-36γ is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36α was detected in microparticles shed from AECs and promoted the production of pro-inflammatory cytokines and chemokines in respiratory cells. IL-36R deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced early accumulation of neutrophils and monocytes/macrophages, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier in despite impaired viral clearance. Taken together, these data indicate that IL-36 ligands exacerbate lung injury during influenza virus infection.