Critical role of IL-1 receptor-associated kinase-M in regulating chemokine-dependent deleterious inflammation in murine influenza pneumonia.
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.
Seki
Masafumi
M
Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Global Centers of Excellence Program, Nagasaki University, Nagasaki, Japan. seki@nagasaki-u.ac.jp
Kohno
Shigeru
S
Newstead
Michael W
MW
Zeng
Xianying
X
Bhan
Urvashi
U
Lukacs
Nicholas W
NW
Kunkel
Steven L
SL
Standiford
Theodore J
TJ
D055371:Acute Lung Injury / Q000276:immunology / Q000473:pathology / Q000628:therapy; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000627:therapeutic use; D002460:Cell Line; D004195:Disease Models, Animal; D004285:Dogs; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology / Q000472:pathogenicity; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D009976:Orthomyxoviridae Infections / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D011024:Pneumonia, Viral / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D023063:Receptors, Interleukin-8B / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; D018836:Inflammation Mediators; D023063:Receptors, Interleukin-8B; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse