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Matrix Metalloprotease 9 Mediates Neutrophil Migration into the Airways in Response to Influenza Virus-Induced Toll-Like Receptor Signaling
Open accessAbstract
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.
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“However, the strategies for differentiation of resident macrophage subsets in the airways and lung tissues are insufficient to distinguish AMs from lung interstitial macrophages or inflammatory monocytic cells invading the lung in response to infections.”
From Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections (2013) · cites this paper as [18]
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Metadata
- Authors
- Bradley, L. M., Douglass, M. F., Chatterjee, D., Akira, S., & Baaten, B. J. G.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Immunology Frontier Research Center, The University of Osaka (JP)
- Corresponding author
- Baaten, Bas J. G.
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-04-05
- Volume
- 8
- Issue
- 4
- Pages
- e1002641
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC3320598
- OpenAlex
- W2014693052
- Cited by
- 207
- References
- 45
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 17 · 2023: 17 · 2022: 14 · 2021: 18 · 2020: 23 · 2019: 12 · 2018: 8 · 2017: 12 · 2016: 17 · 2015: 18 · 2014: 16 · 2013: 15 · 2012: 1
- FWCI
- 11.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG040188, AG040188)
- National Institute of Allergy and Infectious Diseases (P01AI046530, R21AI079584, AI079584)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- MMP-9, neutrophil migration, influenza virus, Toll-like receptor signaling, MyD88, TNF-α, CCL3, basement membrane degradation, extracellular matrix, airway inflammation, viral replication, innate immunity, chemokines
- MeSH terms
- Animals, Cell Movement, Extracellular Matrix, Humans, Neutrophils, Orthomyxoviridae Infections, Respiratory System, Virus Replication, Signal Transduction, Mice, Knockout, Chemokines, Neutrophil Infiltration, Matrix Metalloproteinase 9, Toll-Like Receptors, Mice, Influenza A Virus, H1N1 Subtype, Myeloid Differentiation Factor 88
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