Interleukin-1 receptor-associated kinase M-deficient mice demonstrate an improved host defense during Gram-negative pneumonia.
Pneumonia is a common cause of morbidity and mortality and the most frequent source of sepsis. Bacteria that try to invade normally sterile body sites are recognized by innate immune cells through pattern recognition receptors, among which toll-like receptors (TLRs) feature prominently. Interleukin-1 receptor (IL-1R)-associated kinase (IRAK)-M is a proximal inhibitor of TLR signaling expressed by epithelial cells and macrophages in the lung. To determine the role of IRAK-M in host defense against bacterial pneumonia, IRAK-M-deficient (IRAK-M(-/-)) and normal wild-type (WT) mice were infected intranasally with Klebsiella pneumoniae. IRAK-M mRNA was upregulated in lungs of WT mice with Klebsiella pneumonia, and the absence of IRAK-M resulted in a strongly improved host defense as reflected by reduced bacterial growth in the lungs, diminished dissemination to distant body sites, less peripheral tissue injury and better survival rates. Although IRAK-M(-/-) alveolar macrophages displayed enhanced responsiveness toward intact K. pneumoniae and Klebsiella lipopolysaccharide (LPS) in vitro, IRAK-M(-/-) mice did not show increased cytokine or chemokine levels in their lungs after infection in vivo. The extent of lung inflammation was increased in IRAK-M(-/-) mice shortly after K. pneumoniae infection, as determined by semiquantitative scoring of specific components of the inflammatory response in lung tissue slides. These data indicate that IRAK-M impairs host defense during pneumonia caused by a common gram-negative respiratory pathogen.
Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Jacobien J
JJ
Hoogerwerf
Gerritje J W
GJ
van der Windt
Dana C
DC
Blok
Arie J
AJ
Hoogendijk
Alex F
AF
De Vos
Cornelis
C
van 't Veer
Sandrine
S
Florquin
Koichi S
KS
Kobayashi
Richard A
RA
Flavell
Tom
T
van der Poll
D000818:Animals; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology*; D007109:Immunity / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007710:Klebsiella Infections / Q000150:complications / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000254:growth & development / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000473:pathology; D010587:Phagocytosis; D011014:Pneumonia / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000150:complications / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018925:Chemokines; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse