That cholestatic conditions are accompanied by an enhanced susceptibility to bacterial infection in human and animal models is a known phenomenon. This correlates with the observation that bile acids ...have suppressive effects on cells of innate and adaptive immunity. The present study provides evidence that in human macrophages, bile acids inhibit the LPS-induced expression of proinflammatory cytokines without affecting the expression of the anti-inflammatory cytokine IL-10. This results in a macrophage phenotype that is characterized by an increased IL-10/IL-12 ratio. Correspondingly, bile acids suppress basal phagocytic activity of human macrophages. These effects of bile acids can be mimicked by cAMP, which is presumably induced TGR5-dependently. The data provided further suggest that in primary human macrophages, modulation of the macrophage response toward LPS by bile acids involves activation of CREB, disturbed nuclear translocation of NF-κB, and PKA-dependent enhancement of LPS-induced cFos expression. The increase in cFos expression is paralleled by an enhanced formation of a protein complex comprising cFos and the p65 subunit of NF-κB. In summary, the data provided suggest that in human macrophages, bile acids induce an anti-inflammatory phenotype characterized by an increased IL-10/IL-12 ratio via activation of PKA and thereby, prevent their activation as classically activated macrophages. This bile acid-induced modulation of macrophage function may also be responsible for the experimentally and clinically observed anti-inflammatory and immunosuppressive effects of bile acids.
Monoclonal antibodies (mAb) have been introduced as a promising new therapeutic approach against SARS-CoV-2. At present, there is little experience regarding their clinical effects in patient ...populations underrepresented in clinical trials, e.g. immunocompromised patients. Additionally, it is not well known to what extent SARS-CoV-2 treatment with monoclonal antibodies could trigger the selection of immune escape viral variants.
After identifying immunocompromised patients with viral rebound under treatment with bamlanivimab, we characterized the SARS-CoV-2-isolates by whole genome sequencing. Viral load measurements and sequence analysis were performed consecutively before and after bamlanivimab administration.
After initial decrease of viral load, viral clearance was not achieved in five of six immunocompromised patients treated with bamlanivimab. Instead, viral replication increased again over the course of the following one to two weeks. In these five patients, the E484K substitution – known to confer immune escape – was detected at the time of viral rebound but not before bamlanivimab treatment.
Treatment of SARS-CoV-2 with bamlanivimab in immunocompromised patients results in the rapid development of immune escape variants in a significant proportion of cases. Given that the E484K mutation can hamper natural immunity, the effectiveness of vaccination as well as antibody-based therapies, these findings may have important implications not only for individual treatment decisions but may also pose a risk to general prevention and treatment strategies.
All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease affecting the intrahepatic and extrahepatic biliary tree leading to bile duct strictures, progressive cholestasis, and ...development of liver fibrosis and cirrhosis. The pathogenesis of PSC is still elusive; however, both an immune-mediated injury of the bile ducts as well as increased recruitment of intestinal-primed T lymphocytes to the biliary tracts seem to contribute to disease development and progression. TGR5 (Gpbar-1) is a G-protein-coupled receptor responsive to bile acids, which is expressed in cholangiocytes, intestinal epithelial cells, and macrophages of the liver and intestine as well as in CD14-positive monocytes of the peripheral blood. Activation of TGR5 in biliary epithelial cells promotes chloride and bicarbonate secretion, triggers cell proliferation, and prevents apoptotic cell death. In immune cells, stimulation of TGR5 inhibits cytokine expression and secretion, thus reducing systemic as well as hepatic and intestinal inflammation. The expression pattern of TGR5 in the liver and intestine as well as the potential protective functions of TGR5 suggest a role for this receptor in the pathogenesis of PSC. While mutations in the coding region of the TGR5 gene are too rare to contribute to overall disease susceptibility, the expression and localization of the receptor have not been studied in PSC livers. Pharmacological activation of TGR5 in mice promotes protective mechanisms in biliary epithelial cells and reduces hepatic and systemic inflammation; however, it also provokes pruritus. Further studies are needed to predict the potential benefits as well as side effects of TGR5 agonist treatment in PSC patients.
Hepatic failure is commonly associated with anemia, which may result from gastrointestinal bleeding, vitamin deficiency, or liver‐damaging diseases, such as infection and alcohol intoxication. At ...least in theory, anemia during hepatic failure may result from accelerated clearance of circulating erythrocytes. Here we show that bile duct ligation (BDL) in mice leads to severe anemia despite increased reticulocyte numbers. Bilirubin stimulated suicidal death of human erythrocytes. Mechanistically, bilirubin triggered rapid Ca2+ influx, sphingomyelinase activation, formation of ceramide, and subsequent translocation of phosphatidylserine to the erythrocyte surface. Consistent with our in vitro and in vivo findings, incubation of erythrocytes in serum from patients with liver disease induced suicidal death of erythrocytes in relation to their plasma bilirubin concentration. Consistently, patients with hyperbilirubinemia had significantly lower erythrocyte and significantly higher reticulocyte counts compared to patients with low bilirubin levels. Conclusion: Bilirubin triggers suicidal erythrocyte death, thus contributing to anemia during liver disease. (Hepatology 2015;61:275–284)
Sinusoidal endothelial cells (SEC) constitute a permeable barrier between hepatocytes and blood. SEC are exposed to high concentrations of bile salts from the enterohepatic circulation. Whether SEC ...are responsive to bile salts is unknown. TGR5, a G‐protein–coupled bile acid receptor, which triggers cAMP formation, has been discovered recently in macrophages. In this study, rat TGR5 was cloned and antibodies directed against the C‐terminus of rat TGR5 were developed, which detected TGR5 as a glycoprotein in transfected HepG2‐cells. Apart from Kupffer cells, TGR5 was detected in SEC of rat liver. SEC expressed TGR5 over the entire acinus, whereas endothelial cells of the portal or central veins were not immunoreactive toward TGR5 antibodies. In isolated SEC, TGR5 mRNA and protein were detected by reverse transcription (RT) PCR, immunofluorescence microscopy, and Western blot analysis. Bile salts increased cAMP in isolated SEC and induced mRNA expression of endothelial NO synthase (eNOS), a known cAMP‐dependent gene. In addition, bile acids activated eNOS by phosphorylation of eNOS at amino acid position 1177. In line with eNOS activation, bile acids induced NO production in liver slices. This is the first report on the expression of TGR5 in SEC. Conclusion: The data suggest that SEC are directly responsive toward specific bile salts. Regulation of eNOS in SEC by TGR5 connects bile salts with hepatic hemodynamics. This is of particular importance in cholestatic livers when bile salt concentrations are increased. (HEPATOLOGY 2007;45:695–704.)
Astrocytes play an important role in the pathogenesis of hepatic encephalopathy (HE) and ammonia toxicity, whereas little is known about microglia and neuroinflammation under these conditions. We ...therefore studied the effects of ammonia on rat microglia in vitro and in vivo and analyzed markers of neuroinflammation in post mortem brain tissue from patients with cirrhosis with and without HE and non‐cirrhotic controls. In cultured rat microglia, ammonia stimulated cell migration and induced oxidative stress and an up‐regulation of the microglial activation marker ionized calcium‐binding adaptor molecule‐1 (Iba‐1). Up‐regulation of Iba‐1 was also found in the cerebral cortex from acutely ammonia‐intoxicated rats and in the cerebral cortex from patients with cirrhosis who have HE, but not from patients with cirrhosis who do not have HE. However, ammonia had no effect on microglial glutamate release, prostaglandin synthesis, and messenger RNA (mRNA) levels of inducible nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), and the proinflammatory cytokines interleukin (IL)‐1α/β, tumor necrosis factor α, or IL‐6, whereas in cultured astrocytes ammonia induced the release of glutamate, prostaglandins, and increased IL‐1β mRNA. mRNA and protein expression of iNOS and COX‐2 or mRNA expression of proinflammatory cytokines and chemokine monocyte chemoattractive protein‐1 in cerebral cortex from patients with liver cirrhosis and HE were not different from those found in patients with cirrhosis who did not have HE or control patients without cirrhosis. Conclusion: These data suggest that microglia become activated in experimental hyperammonemia and HE in humans and may contribute to the generation of oxidative stress. However, HE in patients with liver cirrhosis is not associated with an up‐regulation of inflammatory cytokines in cerebral cortex, despite microglia activation. (HEPATOLOGY 2011;)
Management of adults with Alagille syndrome Ayoub, Mohammed D.; Bakhsh, Ahmad A.; Vandriel, Shannon M. ...
Hepatology international,
10/2023, Letnik:
17, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is inherited in an autosomal dominant ...manner in 40% of patients, it carries many implications for genetic counselling of patients and screening of family members. In addition, the considerable variable expression and absence of a clear genotype–phenotype correlation, results in a diverse range of clinical manifestations, even in affected individuals within the same family. With recent therapeutic advancements in cholestasis treatment and the improved survival rates with liver transplantation (LT), many patients with ALGS survive into adulthood. Although LT is curative for liver disease secondary to ALGS, complications secondary to extrahepatic involvement remain problematic lifelong. This review is aimed at providing a comprehensive review of ALGS to adult clinicians who will take over the medical care of these patients following transition, with particular focus on certain aspects of the condition that require lifelong surveillance. We also provide a diagnostic framework for adult patients with suspected ALGS and highlight key aspects to consider when determining eligibility for LT in patients with this syndrome.
The bile acid-activated receptors, including the membrane G protein-coupled receptor TGR5 and nuclear farnesoid X receptor (FXR), have roles in kidney diseases. In this study, we investigated the ...role of TGR5 in renal water handling and the underlying molecular mechanisms.
We used tubule suspensions of inner medullary collecting duct (IMCD) cells from rat kidneys to investigate the effect of TGR5 signaling on aquaporin-2 (AQP2) expression, and examined the
effects of TGR5 in mice with lithium-induced nephrogenic diabetes insipidus (NDI) and
knockout (
) mice.
Activation of TGR5 by lithocholic acid (LCA), an endogenous TGR5 ligand, or INT-777, a synthetic TGR5-specific agonist, induced AQP2 expression and intracellular trafficking in rat IMCD cells
a cAMP-protein kinase A signaling pathway. In mice with NDI, dietary supplementation with LCA markedly decreased urine output and increased urine osmolality, which was associated with significantly upregulated AQP2 expression in the kidney inner medulla. Supplementation with endogenous FXR agonist had no effect. In primary IMCD suspensions from lithium-treated rats, treatment with INT-767 (FXR and TGR5 dual agonist) or INT-777, but not INT-747 (FXR agonist), increased AQP2 expression.
mice exhibited an attenuated ability to concentrate urine in response to dehydration, which was associated with decreased AQP2 expression in the kidney inner medulla. In lithium-treated
mice, LCA treatment failed to prevent reduction of AQP2 expression.
TGR5 stimulation increases renal AQP2 expression and improves impaired urinary concentration in lithium-induced NDI. TGR5 is thus involved in regulating water metabolism in the kidney.
Liver diseases represent a significant global health burden, necessitating the development of reliable biomarkers for early detection, prognosis, and therapeutic monitoring. Extracellular vesicles ...(EVs) have emerged as promising candidates for liver disease biomarkers due to their unique cargo composition, stability, and accessibility in various biological fluids. In this study, we present an optimized workflow for the identification of EVs-based biomarkers in liver disease, encompassing EVs isolation, characterization, cargo analysis, and biomarker validation. Here we show that the levels of microRNAs miR-10a, miR-21, miR-142-3p, miR-150, and miR-223 were different among EVs isolated from patients with nonalcoholic fatty liver disease and autoimmune hepatitis. In addition, IL2, IL8, and interferon-gamma were found to be increased in EVs isolated from patients with cholangiocarcinoma compared with healthy controls. By implementing this optimized workflow, researchers and clinicians can improve the identification and utilization of EVs-based biomarkers, ultimately enhancing liver disease diagnosis, prognosis, and personalized treatment strategies.
PDF
