Mast cell-mediated splanchnic cholestatic inflammation

Aller, María-Ángeles; Martı́nez, Vicente; Arias, Ana; Nava, María-Paz; Cuervas-Mons, Valentín; Vergara, P.; Árias, Jaime

doi:10.1016/j.clinre.2019.02.001

Cited by 9 publications

(8 citation statements)

References 47 publications

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“…(26) Our group demonstrated that MCs infiltrate the liver following injury and perpetuate cholestatic damage (8,9,24) and that stabilization of MCs in cholestatic models results in amelioration of DR, inflammation, and hepatic fibrosis. (27) Aside from traditional receptors, MCs express a number of other receptors and binding sites, including FXRβ and ASBT. (19) Our current work demonstrates that MC-derived FXR/FGF signaling regulates biliary damage and hepatic fibrosis.…”

Section: Bile Ductmentioning

confidence: 99%

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

et al. 2021

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BaCKgRoUND aND aIMS:Cholestasis is characterized by increased total bile acid (TBA) levels, which are regulated by farnesoid X receptor (FXR)/FGF15. Patients with primary sclerosing cholangitis (PSC) typically present with inflammatory bowel disease (IBD). Mast cells (MCs) (i) express FXR and (ii) infiltrate the liver during cholestasis promoting liver fibrosis. In bile-duct-ligated (BDL) MC-deficient mice (B6. Cg-Kit W-sh /HNihrJaeBsmJ [Kit W-sh ]), ductular reaction (DR) and liver fibrosis decrease compared with BDL wild type, and MC injection exacerbates liver damage in normal mice. appRoaCH aND ReSUltS:In this study, we demonstrated that MC-FXR regulates biliary FXR/FGF15, DR, and hepatic fibrosis and alters intestinal FXR/FGF15. We found increased MC number and biliary FXR expression in patients with liver injury compared with control. Histamine and FGF19 serum levels and small heterodimer partner expression increase in patients PSC and PSC-IBD compared with healthy controls. MC injection increased liver damage, DR, inflammation, biliary senescence/senescence-associated secretory phenotype (SASP), fibrosis, and histamine in Kit W-sh mice. Inhibition of MC-FXR before injection reduced these parameters. BDL and Kit W-sh mice injected with MCs displayed increased TBA content, biliary FXR/FGF15, and intestinal inflammation, which decreased in BDL Kit W-sh and Kit W-sh mice injected with MC-FXR. MCs increased ileal FXR/FGF15 expression in Kit W-sh mice that was reduced following FXR inhibition. BDL and multidrug resistance 2/ ATP-binding cassette family 2 member 4 knockout (Mdr2 −/− ) mice, models of PSC, displayed increased intestinal MC infiltration and FXR/FGF15 expression. These were reduced following MC stabilization with cromolyn sodium in Mdr2 −/− mice. In vitro, MC-FXR inhibition decreased biliary proliferation/SASP/FGF and hepatic stellate cell activation. CoNClUSIoNS:Our studies demonstrate that MC-FXR plays a key role in liver damage and DR, including TBA regulation through alteration of intestinal and biliary FXR/ FGF15 signaling. (Hepatology 2021;74:2684-2698. Cholangiocytes are the target cells of cholestatic liver diseases, such as primary sclerosing cholangitis (PSC), which is characterized by

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Section: Bile Ductmentioning

confidence: 99%

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

et al. 2021

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“…It was suggested that MCs migrate into the liver and are activated in patients with cholestasis. Aller et al [22] found that an increase in splanchnic mast cells aggravated the in ammatory response in cholestasis rats. In turn, inhibition of MC mediators decreases ductular reaction and liver brosis [23].…”

Section: Discussionmentioning

confidence: 99%

Identification of a potential miRNA-mRNA regulatory network associated with the pathogenesis of cholestatic liver diseases

Song

Geng

et al. 2022

Preprint

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Background Cholestatic liver diseases (CLDs), including primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), are common digestive diseases that may lead to liver fibrosis, cirrhosis, or even liver failure. However, ursodeoxycholic acid (UDCA), as the first-line drug therapy for PBC, achieves poor results among nearly half of patients. Furthermore, there are few effective ways to cure diseases other than liver transplantation at present. Therefore, it is essential to further explore the disease mechanism in order to find new therapeutic targets. Methods Gene Expression Omnibus (GEO) database (GSE159676) was used to screen differentially expressed hepatic miRNAs between PBC vs. control and PSC vs. control samples, and their interaction was considered as common miRNAs driving CLDs. A miRNA-mRNA network was then constructed based on predicted miRNA-targeted mRNAs. Then enrichment analysis was performed and protein-protein interaction (PPI) networks were constructed. In addition, these DEGs were also validated in models of cholestatic liver injury induced by α -isothiocyanate (ANIT) and bile duct ligation (BDL). Furthermore, the role of hub genes in cholestasis progression, UDCA response, and disease diagnosis were analyzed in GSE166867, GSE79850 and GSE119600, respectively. Results A total of 6 miRNAs and 437 mRNAs were identified as potential mediators in the pathophysiological processes of CLDs. Among them, 8 hub genes were identified (PTPRC, TYROBP, LCP2, RAC2, SYK, TLR2, CD53, and LAPTM5). The functional analysis confirmed that the molecular mechanism was strongly associated with Fc epsilon RI signaling pathway. Combining bioinformatics analysis with animal experimental results, miR-30e and miR-107 were the most significant DE-miRNAs. Additionally, activation of the 8 hub genes was observed in both ANIT-induced cholestasis model and time-course BDL model. Besides, an elevated hepatic SYK level was found in patients with UDCA inefficiency, and SYK in the blood may be an underlying diagnostic indicator for CLDs. Conclusions The present study constructed a miRNA-mRNA network of cholestatic liver diseases, and uncovered that the miR-30e, miR-107 and 8 hub genes could be involved in the pathogenesis of CLDs, providing potential therapeutic targets in CLDs.

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“…Ketotifen, an MC stabilizer, increased hepatic mucosal MC presence in cholestatic rats while decreasing the MC population in the mesenteric lymphatic complex and levels of TGF‐β1 and VEGF. [ 37 ]…”

Section: Diseases Implicated By MC Presence/activationmentioning

confidence: 99%

Mast cells in liver disease progression: An update on current studies and implications

et al. 2021

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Mast cell-mediated splanchnic cholestatic inflammation

Cited by 9 publications

References 47 publications

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

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

Identification of a potential miRNA-mRNA regulatory network associated with the pathogenesis of cholestatic liver diseases

Mast cells in liver disease progression: An update on current studies and implications

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