Mast Cells Induce Ductular Reaction Mimicking Liver Injury in Mice Through Mast Cell–Derived Transforming Growth Factor Beta 1 Signaling: [RETRACTED]

Abstract

Background and Aims Following liver injury, mast cells (MCs) migrate into the liver and are activated in patients with cholestasis. Inhibition of MC mediators decreases ductular reaction (DR) and liver fibrosis. Transforming growth factor beta 1 (TGF‐β1) contributes to fibrosis and promotes liver disease. Our aim was to demonstrate that reintroduction of MCs induces cholestatic injury through TGF‐β1. Approach and Results Wild‐type, KitW‐sh (MC‐deficient), and multidrug resistance transporter 2/ABC transporter B family member 2 knockout mice lacking l‐histidine decarboxylase were injected with vehicle or PKH26‐tagged murine MCs pretreated with 0.01% dimethyl sulfoxide (DMSO) or the TGF‐β1 receptor inhibitor (TGF‐βRi), LY2109761 (10 μM) 3 days before sacrifice. Hepatic damage was assessed by hematoxylin and eosin (H&E) and serum chemistry. Injected MCs were detected in liver, spleen, and lung by immunofluorescence (IF). DR was measured by cytokeratin 19 (CK‐19) immunohistochemistry and F4/80 staining coupled with real‐time quantitative PCR (qPCR) for interleukin (IL)‐1β, IL‐33, and F4/80; biliary senescence was evaluated by IF or qPCR for p16, p18, and p21. Fibrosis was evaluated by sirius red/fast green staining and IF for synaptophysin 9 (SYP‐9), desmin, and alpha smooth muscle actin (α‐SMA). TGF‐β1 secretion/expression was measured by enzyme immunoassay and qPCR. Angiogenesis was detected by IF for von Willebrand factor and vascular endothelial growth factor C qPCR. In vitro, MC‐TGF‐β1 expression/secretion were measured after TGF‐βRi treatment; conditioned medium was collected. Cholangiocytes and hepatic stellate cells (HSCs) were treated with MC‐conditioned medium, and biliary proliferation/senescence was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium and qPCR; HSC activation evaluated for α‐SMA, SYP‐9, and collagen type‐1a expression. MC injection recapitulates cholestatic liver injury characterized by increased DR, fibrosis/TGF‐β1 secretion, and angiogenesis. Injection of MC‐TGF‐βRi reversed these parameters. In vitro, MCs induce biliary proliferation/senescence and HSC activation that was reversed with MCs lacking TGF‐β1. Conclusions Our study demonstrates that reintroduction of MCs mimics cholestatic liver injury and that MC‐derived TGF‐β1 may be a target in chronic cholestatic liver disease.

Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling

“…Interestingly, most mediators secreted by MCs are also SASP components, and several studies have implicated TGF‐β1 in liver disease progression. ( 9,11,29 ) We found that MCs induce IL‐1β expression that was reduced when FXR was inhibited; however, a study by Xiong et al found that obeticholic acid (OCA; FXR agonist), in combination with lipopolysaccharide, ameliorated liver damage and inflammation by decreasing hepatic IL‐1β. ( 30 )…”

Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation

“…The presence of iMCs in HCC was protective in our cohort, but an excess of mast cells can also be protumorigenic. In particular, introduction of mast cells increased hepatic vascular endothelial growth factor (VEGF)‐A and VEGF‐C formation in a transforming growth factor β1‐dependent manner, ( 47 , 48 ) which can favor angiogenesis, epithelial–mesenchymal transition, and tumor growth. Because cholangiocarcinomas contain about 5 times more mast cells compared to HCC, ( 49 ) protumorigenic effects can prevail in cholangiocarcinoma.…”

Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

“…It is apparent that cholangiocyte-derived TGF-β1 is an important factor mediating biliary (autocrine) and liver (paracrine) damage during PSC. Aside from cholangiocytes, mast cells secrete TGF-β1 and induce biliary senescence and other markers of cholestasis (Kyritsi et al, 2021), which is an important feature considering that mast cell migration to portal areas is a key feature and damaging component of cholestasis (Wilcox et al, 1986;Tsuneyama et al, 1999;Jones et al, 2016). Mast cell farnesoid X receptor (FXR) signaling promotes biliary senescence and associated biliary and liver damage in murine models of PSC (Meadows et al, 2021).…”

“…Cholangiocytes are the target of various liver diseases such as fatty liver diseases (nonalcoholic fatty liver disease [NAFLD], non-alcoholic steatohepatitis [NASH]), alcoholic liver disease (ALD) and chronic cholestatic liver diseases including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), biliary atresia, and cholangiocarcinoma. Biliary secretory functions regulate liver inflammation and fibrosis (by both autocrine and paracrine pathways) through secretion of cytokines and other factors which may contribute to liver damage (Kennedy et al, 2021;Kyritsi et al, 2021). Cellular senescence increases in cholangiocytes of PSC patients, likely contributing to disease progression (Tabibian et al, 2014a).…”