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Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice

Authors :
Jack Yang
Ingrid Stroo
Alexey S. Revenko
Joris J. T. H. Roelofs
Tom van der Poll
Alex F. de Vos
Onno J. de Boer
Peter Nürnberg
Brendon P. Scicluna
Chao Ding
Jeff Crosby
Cornelis van 't Veer
Center of Experimental and Molecular Medicine
Experimental Immunology
Graduate School
ACS - Pulmonary hypertension & thrombosis
AII - Infectious diseases
Epidemiology and Data Science
Pathology
ACS - Diabetes & metabolism
ACS - Heart failure & arrhythmias
Infectious diseases
Source :
The Journal of Pathology, Journal of pathology, 250(1), 95-106. John Wiley and Sons Ltd
Publication Year :
2019

Abstract

Prekallikrein (PKK, also known as Fletcher factor and encoded by the gene KLKB1 in humans) is a component of the contact system. Activation of the contact system has been implicated in lethality in fulminant sepsis models. Pneumonia is the most frequent cause of sepsis. We sought to determine the role of PKK in host defense during pneumosepsis. To this end, mice were infected with the common human pathogen Klebsiella pneumoniae via the airways, causing an initially localized infection of the lungs with subsequent bacterial dissemination and sepsis. Mice were treated with a selective PKK-directed antisense oligonucleotide (ASO) or a scrambled control ASO for 3 weeks prior to infection. Host response readouts were determined at 12 or 36 h post-infection, including genome-wide messenger RNA profiling of lungs, or mice were followed for survival. PKK ASO treatment inhibited constitutive hepatic Klkb1 mRNA expression by >80% and almost completely abolished plasma PKK activity. Klkb1 mRNA could not be detected in lungs. Pneumonia was associated with a progressive decline in PKK expression in mice treated with control ASO. PKK ASO administration was associated with a delayed mortality, reduced bacterial burdens, and diminished distant organ injury. While PKK depletion did not influence lung pathology or neutrophil recruitment, it was associated with an upregulation of multiple innate immune signaling pathways in the lungs already prior to infection. Activation of the contact system could not be detected, either during infection in vivo or at the surface of Klebsiella in vitro. These data suggest that circulating PKK confines pro-inflammatory signaling in the lung by a mechanism that does not involve contact system activation, which in the case of respiratory tract infection may impede early protective innate immunity.<br />peer-reviewed

Details

ISSN :
10969896 and 00223417
Volume :
250
Issue :
1
Database :
OpenAIRE
Journal :
The Journal of pathology
Accession number :
edsair.doi.dedup.....e95f4b16cea8f9e9fb94c023155e9b31