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WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice

Citation

Gatica-Andrades, M and Vagenas, D and Kling, J and Nguyen, TTK and Benham, H and Thomas, R and Korner, H and Venkatesh, B and Cohen, J and Blumenthal, A, WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice, Blood Advances, 1, (16) pp. 1274-1286. ISSN 2473-9529 (2017) [Refereed Article]


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Copyright 2017 by American Society of Hematology

DOI: doi:10.1182/bloodadvances.2017006163

Abstract

Improved understanding of the molecular mechanisms underlying dysregulated inflammatory responses in severe infection and septic shock is urgently needed to improve patient management and identify new therapeutic opportunities. The WNT signaling pathway has been implicated as a novel constituent of the immune response to infection, but its contribution to the host response in septic shock is unknown. Although individual WNT proteins have been ascribed pro- or anti-inflammatory functions, their concerted contributions to inflammation in vivo remain to be clearly defined. Here we report differential expression of multiple WNT ligands in whole blood of patients with septic shock and reveal significant correlations with inflammatory cytokines. Systemic challenge of mice with lipopolysaccharide (LPS) similarly elicited differential expression of multiple WNT ligands with correlations between WNT and cytokine expression that partially overlap with the findings in human blood. Molecular regulators of WNT expression during microbial encounter in vivo are largely unexplored. Analyses in gene-deficient mice revealed differential contributions of Toll-like receptor signaling adaptors, a positive role for tumor necrosis factor, but a negative regulatory role for interleukin (IL)-12/23p40 in the LPS-induced expression of Wnt5b, Wnt10a, Wnt10b, and Wnt11. Pharmacologic targeting of bottlenecks of the WNT network, WNT acylation and β-catenin activity, diminished IL-6, tumor necrosis factor, and IL-12/23p40 in serum of LPS-challenged mice and cultured splenocytes, whereas IL-10 production remained largely unaffected. Taken together, our data support the conclusion that the concerted action of WNT proteins during severe infection and septic shock promotes inflammation, and that this is, at least in part, mediated by WNT/β-catenin signaling.

Item Details

Item Type:Refereed Article
Keywords:WNT ligands, septic shock, endotoxemia, inflammatory cytokines
Research Division:Medical and Health Sciences
Research Group:Immunology
Research Field:Immunology not elsewhere classified
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Infectious Diseases
UTAS Author:Korner, H (Professor Heinrich Korner)
ID Code:124051
Year Published:2017
Web of Science® Times Cited:11
Deposited By:Menzies Institute for Medical Research
Deposited On:2018-02-07
Last Modified:2018-07-23
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