Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
PLoS Pathog. 2012;8(4):e1002641. doi: 10.1371/journal.ppat.1002641. Epub 2012 Apr 5.
The early inflammatory response to influenza virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which neutrophils gain entry to the respiratory tract and their role during pathogenesis remain unclear. Here, we report that neutrophils significantly contributed to morbidity in a pathological mouse model of influenza virus infection. Using extensive immunohistochemistry, bone marrow transfers, and depletion studies, we identified neutrophils as the predominant pulmonary cellular source of the gelatinase matrix metalloprotease (MMP) 9, which is capable of digesting the extracellular matrix. Furthermore, infection of MMP9-deficient mice showed that MMP9 was functionally required for neutrophil migration and control of viral replication in the respiratory tract. Although MMP9 release was toll-like receptor (TLR) signaling-dependent, MyD88-mediated signals in non-hematopoietic cells, rather than neutrophil TLRs themselves, were important for neutrophil migration. These results were extended using multiplex analyses of inflammatory mediators to show that neutrophil chemotactic factor, CCL3, and TNFα were reduced in the Myd88⁻/⁻ airways. Furthermore, TNFα induced MMP9 secretion by neutrophils and blocking TNFα in vivo reduced neutrophil recruitment after infection. Innate recognition of influenza virus therefore provides the mechanisms to induce recruitment of neutrophils through chemokines and to enable their motility within the tissue via MMP9-mediated cleavage of the basement membrane. Our results demonstrate a previously unknown contribution of MMP9 to influenza virus pathogenesis by mediating excessive neutrophil migration into the respiratory tract in response to viral replication that could be exploited for therapeutic purposes.
流感病毒感染的早期炎症反应导致严重的肺部疾病，并继续对人类健康构成严重威胁。中性粒细胞进入呼吸道的机制及其在发病机制中的作用仍不清楚。在这里，我们报告中性粒细胞在流感病毒感染的病理性小鼠模型中显著导致发病。通过广泛的免疫组织化学、骨髓转移和耗竭研究，我们确定中性粒细胞是呼吸道中明胶酶基质金属蛋白酶（MMP）9的主要肺细胞来源，MMP9 能够消化细胞外基质。此外，MMP9 缺陷型小鼠的感染表明 MMP9 对于中性粒细胞迁移和控制呼吸道中的病毒复制是功能必需的。尽管 MMP9 的释放依赖于 Toll 样受体（TLR）信号，但非造血细胞中的 MyD88 介导的信号，而不是中性粒细胞 TLR 本身，对于中性粒细胞迁移是重要的。使用炎症介质的多重分析扩展了这些结果，表明中性粒细胞趋化因子 CCL3 和 TNFα在 Myd88⁻/⁻气道中减少。此外，TNFα诱导中性粒细胞分泌 MMP9，体内阻断 TNFα可减少感染后中性粒细胞的募集。因此，流感病毒的先天识别提供了通过趋化因子募集中性粒细胞并通过 MMP9 介导的基底膜裂解来实现其在组织内运动的机制。我们的结果表明 MMP9 以前未知的对流感病毒发病机制的贡献，通过介导过度的中性粒细胞迁移到呼吸道中以响应病毒复制，这可能被用于治疗目的。
