Journal
JOURNAL OF IMMUNOLOGY
Volume 184, Issue 3, Pages 1410-1418Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0901709
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Funding
- Japanese Society for the Promotion of Science [21790774]
- National Institutes of Health/National Heart, Lung, and Blood Institute [HL57243, P50 HL074024]
- Grants-in-Aid for Scientific Research [21790774] Funding Source: KAKEN
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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. The Journal of Immunology, 2010,184: 1410-1418.
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