Abstract
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.
Highlights
Influenza viruses are highly contagious and cause an average of 226,000 hospitalizations and 36,000 deaths in yearly epidemics [1]
Whereas this process results in full maturation of dendritic cells (DCs), activation and recruitment of antigen-specific T cells, and adequate antiinfluenza humoral responses [9,10], aberrant signaling has been suggested to play a key role in mediating lung pathology that is characterized by excess inflammation and pulmonary destruction [4]
We demonstrated that MMP9 secretion correlated with morbidity, since neutrophil depletion significantly reduced MMP9 exocytosis (Figure 3C), confirming our results that MMP9 was predominantly produced by neutrophils after influenza virus infection (Figure 2C)
Summary
Influenza viruses are highly contagious and cause an average of 226,000 hospitalizations and 36,000 deaths in yearly epidemics [1]. Severe complications arising from pandemic influenza or highly pathogenic avian viruses are often associated with rapid, massive inflammatory cell infiltration [4]. TLR3/7 signaling induces an inflammatory response that promotes a cascade of immune processes that regulate cellular recruitment and function, including the induction of cytokines and chemokines. Whereas this process results in full maturation of dendritic cells (DCs), activation and recruitment of antigen-specific T cells, and adequate antiinfluenza humoral responses [9,10], aberrant signaling has been suggested to play a key role in mediating lung pathology that is characterized by excess inflammation and pulmonary destruction [4]
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