Tags

Type your tag names separated by a space and hit enter

Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice.
J Pathol 2020; 250(1):95-106JP

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

Authors+Show Affiliations

Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China. Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Department of Clinical Epidemiology and Biostatistics, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Department of Pathology, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Department of Pathology, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, CA, USA.Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, CA, USA.Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Division of Infectious Diseases, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31595971

Citation

Ding, Chao, et al. "Prekallikrein Inhibits Innate Immune Signaling in the Lung and Impairs Host Defense During Pneumosepsis in Mice." The Journal of Pathology, vol. 250, no. 1, 2020, pp. 95-106.
Ding C, Scicluna BP, Stroo I, et al. Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice. J Pathol. 2020;250(1):95-106.
Ding, C., Scicluna, B. P., Stroo, I., Yang, J., Roelofs, J. J., de Boer, O. J., ... van der Poll, T. (2020). Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice. The Journal of Pathology, 250(1), pp. 95-106. doi:10.1002/path.5354.
Ding C, et al. Prekallikrein Inhibits Innate Immune Signaling in the Lung and Impairs Host Defense During Pneumosepsis in Mice. J Pathol. 2020;250(1):95-106. PubMed PMID: 31595971.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice. AU - Ding,Chao, AU - Scicluna,Brendon P, AU - Stroo,Ingrid, AU - Yang,Jack, AU - Roelofs,Joris Jth, AU - de Boer,Onno J, AU - de Vos,Alex F, AU - Nürnberg,Peter, AU - Revenko,Alexey S, AU - Crosby,Jeff, AU - Van't Veer,Cornelis, AU - van der Poll,Tom, Y1 - 2019/11/25/ PY - 2019/05/03/received PY - 2019/09/20/revised PY - 2019/10/01/accepted PY - 2019/10/10/pubmed PY - 2019/10/10/medline PY - 2019/10/10/entrez KW - Klebsiella KW - contact system KW - innate immunity KW - lungs KW - pneumonia KW - prekallikrein KW - sepsis SP - 95 EP - 106 JF - The Journal of pathology JO - J. Pathol. VL - 250 IS - 1 N2 - 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. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. SN - 1096-9896 UR - https://www.unboundmedicine.com/medline/citation/31595971/Prekallikrein_inhibits_innate_immune_signaling_in_the_lung_and_impairs_host_defense_during_pneumosepsis_in_mice_ L2 - https://doi.org/10.1002/path.5354 DB - PRIME DP - Unbound Medicine ER -