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Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice
- 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
- Subjects :
- 0301 basic medicine
Septicemia -- Diagnosis
Male
Fulminant
Communicable diseases -- Case studies
Pathology and Forensic Medicine
Sepsis
sepsis
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
In vivo
Klebsiella
medicine
Pneumonia, Bacterial
Animals
pneumonia
Lung
innate immunity
lungs
Lungs -- Diseases
Original Paper
Innate immune system
business.industry
prekallikrein
Oligonucleotides, Antisense
contact system
medicine.disease
Natural immunity
Original Papers
Immunity, Innate
Klebsiella Infections
Mice, Inbred C57BL
Disease Models, Animal
Klebsiella pneumoniae
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Immunology
Pneumonia -- Diagnosis
Signal transduction
business
Respiratory tract
Signal Transduction
Subjects
Details
- ISSN :
- 10969896 and 00223417
- Volume :
- 250
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- The Journal of pathology
- Accession number :
- edsair.doi.dedup.....e95f4b16cea8f9e9fb94c023155e9b31