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Interleukin-1 receptor-associated kinase M-deficient mice demonstrate an improved host defense during Gram-negative pneumonia.
Mol Med 2012; 18:1067-75MM

Abstract

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.

Authors+Show Affiliations

Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22729155

Citation

Hoogerwerf, Jacobien J., et al. "Interleukin-1 Receptor-associated Kinase M-deficient Mice Demonstrate an Improved Host Defense During Gram-negative Pneumonia." Molecular Medicine (Cambridge, Mass.), vol. 18, 2012, pp. 1067-75.
Hoogerwerf JJ, van der Windt GJ, Blok DC, et al. Interleukin-1 receptor-associated kinase M-deficient mice demonstrate an improved host defense during Gram-negative pneumonia. Mol Med. 2012;18:1067-75.
Hoogerwerf, J. J., van der Windt, G. J., Blok, D. C., Hoogendijk, A. J., De Vos, A. F., van 't Veer, C., ... van der Poll, T. (2012). Interleukin-1 receptor-associated kinase M-deficient mice demonstrate an improved host defense during Gram-negative pneumonia. Molecular Medicine (Cambridge, Mass.), 18, pp. 1067-75. doi:10.2119/molmed.2011.00450.
Hoogerwerf JJ, et al. Interleukin-1 Receptor-associated Kinase M-deficient Mice Demonstrate an Improved Host Defense During Gram-negative Pneumonia. Mol Med. 2012 Sep 25;18:1067-75. PubMed PMID: 22729155.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2012/09/25/ PY - 2011/11/19/received PY - 2012/06/18/accepted PY - 2012/6/26/entrez PY - 2012/6/26/pubmed PY - 2013/2/7/medline SP - 1067 EP - 75 JF - Molecular medicine (Cambridge, Mass.) JO - Mol. Med. VL - 18 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. SN - 1528-3658 UR - https://www.unboundmedicine.com/medline/citation/22729155/Interleukin_1_receptor_associated_kinase_M_deficient_mice_demonstrate_an_improved_host_defense_during_Gram_negative_pneumonia_ L2 - https://doi.org/10.2119/molmed.2011.00450 DB - PRIME DP - Unbound Medicine ER -