Critical role of IL-1 receptor-associated kinase-M in regulating chemokine-dependent deleterious inflammation in murine influenza pneumonia.

Abstract

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.

• Authors: Masafumi Seki, Shigeru Kohno, Michael W Newstead, Xianying Zeng, Urvashi Bhan, Nicholas W Lukacs, Steven L Kunkel, Theodore J Standiford
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 184 Issue 3 Pg. 1410-8 (Feb 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20042589 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Inflammation Mediators
• Receptors, Interleukin-8B
• Interleukin-1 Receptor-Associated Kinases
• Irak3 protein, mouse

Topics

• Acute Lung Injury (immunology, pathology, therapy)
• Animals
• Antibodies (administration & dosage, therapeutic use)
• Cell Line
• Disease Models, Animal
• Dogs
• Inflammation Mediators (metabolism, physiology)
• Influenza A Virus, H1N1 Subtype (immunology, pathogenicity)
• Interleukin-1 Receptor-Associated Kinases (biosynthesis, deficiency, genetics, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophils (immunology, pathology)
• Orthomyxoviridae Infections (enzymology, immunology, pathology, therapy)
• Pneumonia, Viral (enzymology, immunology, pathology, therapy)
• Receptors, Interleukin-8B (immunology, physiology)