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The role of macrophage-inducible c-type lectin in different stages of chronic liver disease

  • The macrophage-inducible C-type lectin (mincle) is part of the innate immune system and acts as a pattern recognition receptor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs). Ligand binding induces mincle activation which consequently interacts with the signaling adapter Fc receptor, SYK, and NF-kappa-B. There is also evidence that mincle expressed on macrophages promotes intestinal barrier integrity. However, little is known about the role of mincle in hepatic fibrosis, especially in more advanced disease stages. Mincle expression was measured in human liver samples from cirrhotic patients and donors collected at liver transplantation and in patients undergoing bariatric surgery. Human results were confirmed in rodent models of cirrhosis and acute-on-chronic liver failure (ACLF). In these models, the role of mincle was investigated in liver samples as well as in peripheral blood monocytes (PBMC), tissues from the kidney, spleen, small intestine, and heart. Additionally, mincle activation was stimulated in experimental non-alcoholic steatohepatitis (NASH) by treatment with mincle agonist trehalose-6,6-dibehenate (TDB). In human NASH, mincle is upregulated with increased collagen production. In ApoE deficient mice fed high-fat western diet (NASH model), mincle activation significantly increases hepatic collagen production. In human cirrhosis, mincle expression is also significantly upregulated. Furthermore, mincle expression is associated with the stage of chronic liver disease. This could be confirmed in rat models of cirrhosis and ACLF. ACLF was induced by LPS injection in cirrhotic rats. While mincle expression and downstream signaling via FC receptor gamma, SYK, and NF-kappa-B are upregulated in the liver, they are downregulated in PBMCs of these rats. Although mincle expressed on macrophages might be beneficial for intestinal barrier integrity, it seems to contribute to inflammation and fibrosis once the intestinal barrier becomes leaky in advanced stages of chronic liver disease.

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Author:Robert SchierwagenORCiDGND, Frank Erhard UschnerORCiDGND, Cristina OrtizORCiD, Sandra Torres NúñezORCiD, Maximilian BrolORCiDGND, Olaf Tyc, Wenyi GuORCiDGND, Christian Grimm, Stefan ZeuzemORCiDGND, Andreas Plamper, Philipp Pfeifer, Sebastian Zimmer, Christoph WelschORCiDGND, Liliana SchäferORCiD, Karl P. Rheinwalt, Joan Clària, Vicente ArroyoORCiD, Jonel TrebickaORCiDGND, Sabine KleinORCiD
URN:urn:nbn:de:hebis:30:3-550655
DOI:https://doi.org/10.3389/fimmu.2020.01352
ISSN:1664-3224
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Pranoti Mandrekar
Document Type:Article
Language:English
Year of Completion:2020
Date of first Publication:2020/07/07
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/07/15
Tag:ACLF; NASH; bacterial translocation; fibrosis; inflammation
Volume:11
Issue:Art. 1352
Page Number:9
First Page:1
Last Page:9
Note:
Copyright © 2020 Schierwagen, Uschner, Ortiz, Torres, Brol, Tyc, Gu, Grimm, Zeuzem, Plamper, Pfeifer, Zimmer, Welsch, Schaefer, Rheinwalt, Clària, Arroyo, Trebicka and Klein. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
HeBIS-PPN:467555184
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0