Universität zu Köln

Ding, Chao, Scicluna, Brendon P., Stroo, Ingrid, Yang, Jack, Roelofs, Joris J. T. H., de Boer, Onno J., de Vos, Alex F., Nuernberg, Peter, Revenko, Alexey S., Crosby, Jeff, van't Veer, Cornelis and van der Poll, Tom (2020). Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice. J. Pathol., 250 (1). S. 95 - 107. HOBOKEN: WILEY. ISSN 1096-9896

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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. (c) 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ding, Chao UNSPECIFIED UNSPECIFIED UNSPECIFIED Scicluna, Brendon P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stroo, Ingrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Yang, Jack UNSPECIFIED UNSPECIFIED UNSPECIFIED Roelofs, Joris J. T. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Boer, Onno J. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Vos, Alex F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Revenko, Alexey S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Crosby, Jeff UNSPECIFIED UNSPECIFIED UNSPECIFIED van't Veer, Cornelis UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Poll, Tom UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-127178
DOI:	10.1002/path.5354
Journal or Publication Title:	J. Pathol.
Volume:	250
Number:	1
Page Range:	S. 95 - 107
Date:	2020
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1096-9896
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PNEUMONIA-DERIVED SEPSIS; GRAM-NEGATIVE PNEUMONIA; FACTOR-XII; KLEBSIELLA-PNEUMONIAE; CONTACT SYSTEM; PLASMA KALLIKREIN; COAGULATION; PULMONARY; INFECTION; CONTRIBUTES Multiple languages Oncology; Pathology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12717