Interleukin-1 Receptor-Associated Kinase M-Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia

Jacobien J Hoogerwerf,Richard A Flavell,Gerritje J W Van Der Windt,Arie J Hoogendijk,Sandrine Florquin,Koichi S Kobayashi,Alex F De Vos,Cornelis Van’T Veer,Tom Van Der Poll,Dana C Blok

doi:10.2119/molmed.2011.00450

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.

Highlights

Toll-like receptors (TLRs) occupy a central position in the initiation of cellular innate immune responses [1]
We argued that IRAK-M could play a pivotal role in host defense against primary bacterial pneumonia, considering its expression in the two most prominent resident cells in the bronchoalveolar space, that is, macrophages and respiratory epithelial cells [6,9,11,12], and its central place in TLR signaling
We infected WT mice with K. pneumoniae via the airways using an established model of severe pneumonia [13,14] and determined pulmonary IRAK-M expression at mRNA and protein level

Summary

INTRODUCTION

Toll-like receptors (TLRs) occupy a central position in the initiation of cellular innate immune responses [1]. Considering its central position in the regulation of TLR and IL-1/IL-18 signaling, IRAK-M likely plays an important role in the host response to bacterial infection. In mice with polymicrobial abdominal sepsis, enhanced IRAK-M expression in pulmonary macrophages contributed to a diminished capacity of these cells to respond to Pseudomonas aeruginosa ex vivo, which resulted in a strongly impaired host defense response during secondary (following abdominal sepsis) Pseudomonas pneumonia [9]. We argued that IRAK-M could play a pivotal role in host defense against primary bacterial pneumonia, considering its expression in the two most prominent resident cells in the bronchoalveolar space, that is, macrophages and respiratory epithelial cells [6,9,11,12], and its central place in TLR signaling. Here we induced gram-negative (using Klebsiella pneumoniae) pneumonia in IRAK-M–/– and WT mice, seeking to establish the contribution of this negative TLR regulator in antibacterial defense in the previously healthy host

MATERIALS AND METHODS

RESULTS

DISCUSSION

CONCLUSION