title: Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling.
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.
authors.affiliation: Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Bradley
authors.forename: Mia F
authors.initials: MF
authors.lastname: Douglass
authors.forename: Dhrubamitra
authors.initials: D
authors.lastname: Chatterjee
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Bas J G
authors.initials: BJ
authors.lastname: Baaten
mesh_terms: D000818:Animals; D002465:Cell Movement; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012137:Respiratory System / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D018925:Chemokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse