Galectin-3 Enhances Avian H5N1 Influenza A Virus-Induced Pulmonary Inflammation by Promoting NLRP3 Inflammasome Activation
Galectin-3 Enhances Avian H5N1 Influenza A Virus-Induced Pulmonary Inflammation by Promoting NLRP3 Inflammasome Activation
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DOI：
10.1016/j.ajpath.2017.12.014
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发表时间：
2018-04-01
影响因子：
6
通讯作者：
Liu, Fu-Tong
中科院分区：
文献类型：
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作者：
Chen, Yu-Jung;Wang, Sheng-Fan;Liu, Fu-Tong
高致病性甲型H5N1禽流感病毒会导致人类肺炎和急性呼吸窘迫综合征。病毒引起的过度炎症反应导致严重疾病和高死亡率。 Galectin-3 是一种广泛分布于免疫细胞和上皮细胞中的 β-半乳糖苷结合蛋白，可调节多种免疫功能并调节微生物感染。在这里，我们描述了 H5N1 流感病毒攻击后小鼠肺组织中半乳糖凝集素 3 的上调。我们研究了内源性半乳糖凝集素 3 对 H5N1 感染的影响，发现半乳糖凝集素 3 敲除 (Gal-3K0) 小鼠感染后的存活率与野生型 (WT) 小鼠相当。与感染的WT小鼠相比，感染的Gal-3K0小鼠肺部炎症较少，支气管肺泡灌洗液中IL-1β水平降低。此外，与 WT 小鼠的骨髓源性巨噬细胞 (BMM) 相比，Gal-3K0 小鼠的骨髓源性巨噬细胞 (BMM) 表现出含有 caspase 相关募集结构域的凋亡相关斑点样蛋白寡聚化减少，并分泌较少的 IL-1 β。然而，在两种基因型的 BMM 中观察到核苷酸寡聚结构域样受体蛋白 3 (NLRP3) 的炎症小体成分的水平相似。免疫共沉淀数据表明感染 H5N1 的 BMM 中半乳糖凝集素 3 和 NLRP3 存在相互作用。半乳糖凝集素 3 和含有 caspase 相关募集结构域复合物的 NLRP3/凋亡相关斑点样蛋白之间也观察到了关联。综合而言，我们的结果表明，内源性半乳糖凝集素 3 通过促进宿主炎症反应并通过与 NLRP3 相互作用调节巨噬细胞 IL-1 β 的产生来增强 H5N1 感染的效果。
Highly pathogenic avian influenza A H5N1 virus causes pneumonia and acute respiratory distress syndrome in humans. Virus-induced excessive inflammatory response contributes to severe disease and high mortality rates. Galectin-3, a beta-galactoside-binding protein widely distributed in immune and epithelial cells, regulates various immune functions and modulates microbial infections. Here, we describe galectin-3 up-regulation in mouse lung tissue after challenges with the H5N1 influenza virus. We investigated the effects of endogenous galectin-3 on H5N1 infection and found that survival of galectin-3 knockout (Gal-3K0) mice was comparable with wild-type (WT) mice after infections. Compared with infected WT mice, infected Gal-3K0 mice exhibited less inflammation in the lungs and reduced IL-1 beta levels in bronchoalveolar Lavage fluid. In addition, the bone marrow-derived macrophages (BMMs) from Gal-3K0 mice exhibited reduced oligomerization of apoptosis-associated speck-Like proteins containing caspase-associated recruitment domains and secreted Less IL-1 beta compared with BMMs from WT mice. However, similar levels of the inflammasome component of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) were observed in two genotypes of BMMs. Coimmunoprecipitation data indicated galectin-3 and NLRP3 interaction in BMMs infected with H5N1. An association was also observed between galectin-3 and NLRP3/apoptosis-associated speck-like proteins containing caspase-associated recruitment domain complex. Combined, our results suggest that endogenous galectin-3 enhances the effects of H5N1 infection by promoting host inflammatory responses and regulating IL-1 beta production by macrophages via interaction with NLRP3.