Abstract
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.
Highlights
The macrophage-inducible Ca2+-dependent lectin receptor is a primary component of the innate immune response and acts as a sensor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPS) and is expressed mainly on cell types of the myeloid lineage [1]
There are only a few reports published about the role of mincle in fibrosis and none about its role in more advanced stages of chronic liver injury, this study aims to assess the role of mincle in cirrhosis and acute-on-chronic liver failure (ACLF) in the liver and in other organs that are highly affected by systemic inflammation
This study describes for the first time the mincle expression in different stages of chronic liver disease especially in more advanced stages of chronic liver disease and ACLF
Summary
The macrophage-inducible Ca2+-dependent lectin receptor (mincle) is a primary component of the innate immune response and acts as a sensor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPS) and is expressed mainly on cell types of the myeloid lineage (e.g., macrophages) [1]. Binding of the ligand to mincle leads to interaction with the signaling adapter FC receptor gamma chain (FCER1G) [3]. The formed receptor complex enables intracellular signaling molecules to dock on the immunoreceptor tyrosine-based activation motif (ITAM) and thereby transduce signaling in immune cells. The downstream signaling of the complex proceeds inter alia via spleen associated tyrosine kinase (SYK) and the nuclear factor kappa-light-chain-enhancer (NF-κB) to induce the gene expression of pro-inflammatory cytokines, chemokines, and enzymes [4, 5]. Mincle stimulation promotes the inflammatory phenotype of mainly M1 macrophages [6, 7]
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