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J Immunol. 2009 Dec 30. [Epub ahead of print]
Critical Role of IL-1 Receptor-Associated Kinase-M in Regulating Chemokine-Dependent Deleterious Inflammation in Murine Influenza Pneumonia.
Seki M, Kohno S, Newstead MW, Zeng X, Bhan U, Lukacs NW, Kunkel SL, Standiford TJ. - Department of Molecular Microbiology and Immunology, Second Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Global Centers of Excellence Program, Nagasaki University, Nagasaki, Japan;
Influenza virus is a common cause of respiratory infection and morbidity, which is often due to deleterious host immune responses directed against the pathogen. We investigated the role of IL-1 receptor-associated kinase-M (IRAK-M), an inhibitor of MyD88-dependent TLR signaling, in modulating the innate inflammatory response during influenza pneumonia using a murine model. The intranasal administration of influenza resulted in the upregulation of IRAK-M mRNA and protein levels in the lungs within 2 d after infectious challenge. Pulmonary influenza infection in mice deficient in IRAK-M (IRAK-M(-/-)) resulted in substantially increased mortality compared with similarly treated wild-type animals. Increased mortality in IRAK-M(-/-) mice was associated with enhanced early influx of neutrophils, high permeability edema, apoptosis of lung epithelial cells, markedly increased expression of inflammatory cytokines/chemokines, and release of neutrophil-derived enzymes, including myeloperoxidase and neutrophil elastase. Early viral clearance was not different in mutant mice, whereas viral titers in lungs and blood were significantly higher in IRAK-M(-/-)mice compared with wild-type animals. Increased lethality observed in IRAK-M(-/-) mice after influenza challenge was abrogated by Ab-mediated blockade of CXCR2. Collectively, our findings indicate that IRAK-M is critical to preventing deleterious neutrophil-dependent lung injury during influenza infection of the respiratory tract.
PMID: 20042589 [PubMed - as supplied by publisher]
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Critical Role of IL-1 Receptor-Associated Kinase-M in Regulating Chemokine-Dependent Deleterious Inflammation in Murine Influenza Pneumonia.
Seki M, Kohno S, Newstead MW, Zeng X, Bhan U, Lukacs NW, Kunkel SL, Standiford TJ. - Department of Molecular Microbiology and Immunology, Second Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Global Centers of Excellence Program, Nagasaki University, Nagasaki, Japan;
Influenza virus is a common cause of respiratory infection and morbidity, which is often due to deleterious host immune responses directed against the pathogen. We investigated the role of IL-1 receptor-associated kinase-M (IRAK-M), an inhibitor of MyD88-dependent TLR signaling, in modulating the innate inflammatory response during influenza pneumonia using a murine model. The intranasal administration of influenza resulted in the upregulation of IRAK-M mRNA and protein levels in the lungs within 2 d after infectious challenge. Pulmonary influenza infection in mice deficient in IRAK-M (IRAK-M(-/-)) resulted in substantially increased mortality compared with similarly treated wild-type animals. Increased mortality in IRAK-M(-/-) mice was associated with enhanced early influx of neutrophils, high permeability edema, apoptosis of lung epithelial cells, markedly increased expression of inflammatory cytokines/chemokines, and release of neutrophil-derived enzymes, including myeloperoxidase and neutrophil elastase. Early viral clearance was not different in mutant mice, whereas viral titers in lungs and blood were significantly higher in IRAK-M(-/-)mice compared with wild-type animals. Increased lethality observed in IRAK-M(-/-) mice after influenza challenge was abrogated by Ab-mediated blockade of CXCR2. Collectively, our findings indicate that IRAK-M is critical to preventing deleterious neutrophil-dependent lung injury during influenza infection of the respiratory tract.
PMID: 20042589 [PubMed - as supplied by publisher]
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