TY - JOUR
T1 - Interleukin-1 Receptor-Associated Kinase M-Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia
AU - Hoogerwerf, Jacobien J.
AU - van der Windt, Gerritje J. W.
AU - Blok, Dana C.
AU - Hoogendijk, Arie J.
AU - de Vos, Alex F.
AU - van 't Veer, Cornelis
AU - Florquin, Sandrine
AU - Kobayashi, Koichi S.
AU - Flavell, Richard A.
AU - van der Poll, Tom
PY - 2012
Y1 - 2012
N2 - 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. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00450
AB - 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. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00450
U2 - https://doi.org/10.2119/molmed.2011.00450
DO - https://doi.org/10.2119/molmed.2011.00450
M3 - Article
C2 - 22729155
SN - 1076-1551
VL - 18
SP - 1067
EP - 1075
JO - Molecular medicine (Cambridge, Mass.)
JF - Molecular medicine (Cambridge, Mass.)
IS - 7
ER -