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(A) Serum levels of IFN-γ and IL-17A in B6 and IL-23p19−/− mice 2 and 4 weeks after initial 2OA-BSA immunization. (B) Production of IFN-γ and IL-17A in supernatant fluids of cultured splenic and hepatic MNCs (n = 4) with anti-CD3/CD28 mAbs for 3 days (C) inflammatory cytokines in extracted liver protein from WT mice (n = 8) and IL-23p19−/− (n = 8) mice. *p<0.05, **p<0.01, ***p<0.001.
Source publication
Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, with the most highly directed and specific autoantibody in both murine and human autoimmunity, the anti-mitochondrial autoantibody (AMA). However, therapeutic advances in this disease have lagged behind. Herein we have taken advantage of our unique model of murine PBC in whic...
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Citations
... Therefore, our study con rmed the immune protective function of probiotics in the gut likely, but not exclusively, by improving gut epithelial barrier function. (CXCR3) promote the differentiation of CD4 + T cells into Th17 cells, the main source of IL-17A production that are involved in anti-fungal infection (Zelante et al., 2009;Kawata et al., 2013;Chen et al., 2021;Sawada et al., 2021). Although the majority of colonic fungal distribution did not signi cantly differ between NX and DLY piglets, the remaining fungal species in NX piglet may be involved in the regulation of IL17F expression. ...
Background
NingXiang (NX) pig has been characterized as one of the best Chinese indigenous pig breeds, with high fertility and disease resistance.
However, its intestinal gene expression and gut microbial characteristics have not been studied.
Results
Here, we delineated and compared the profile of intestinal microbiome and transcriptome between NX and Duroc × Landrace × Large white (DLY) piglets by integrating metagenomic and transcriptomic analyses. We found that the abundance of several colonic Bacteroides species (B. fragilis, B. thetaiotaomicron and B. sp_PHL_2737), Prevotella species (P. intermedia, P. dentalis and P. enoeca), Clostridium species (C. scindens, C. butyricum and C. botulinum), Anaerrobutyricum and Lactobacillus_saerimneri are significantly increased in NX piglets than DLY piglets. Additionally, several archaea and fungal species were also dominantly enriched in the colon of NX piglets. Then, we identified some unique colonic bacterial species that may act as characteristics of these two pig breeds. Functional analyses of NX piglets-enriched microbes revealed their dominant function in methane, glycolysis and gluconeogenesis metabolism. Strikingly, the composition and function of the gut microbiota were significantly correlated with growth performance both in NX and DLY piglets. Finally, our mRNA-sequencing revealed the distinct intestinal gene expression pattern between NX and DLY piglets, and NX piglets exhibit improved intestinal barrier function and varied immune features than DLY piglets.
Conclusion
Together, our study revealed the characteristics of the gut microbiota and intestinal gene expression in NX piglets, providing the potential to explore its mechanisms in disease resistance and gut development.
... Transplantation of human umbilical cord-derived mesenchymal stem cells into 2-OA-bovine serum albumin (BSA) mice considerably ameliorates hepatic inflammation by dampening the Th1/Th17 response [62]. Moreover, the absence of Th17 cells inhibits hepatic accumulation of IFN-γ-producing cells, but IL-23/Th17 cells promote Th1-mediated immunopathology [63]. Th2 cells and their secreted cytokines are also implicated in PBC pathogenesis. ...
Background
Primary biliary cholangitis (PBC) is an autoimmune liver disease. The aetiology of PBC remains unclear, and its pathogenesis is complex. Animal models are essential to clarify the pathogenesis of PBC and explore the occurrence of early events.
Main body
Herein, we review recent research progress in PBC animal models, including genetically modified, chemically inducible, biologically inducible, and protein-immunised models. Although these animal models exhibit several immunological and pathological features of PBC, they all have limitations that constrain further research and weaken their connection with clinical practice.
Conclusion
The review will benefit efforts to understand and optimise animal models in order to further clarify PBC pathogenesis and molecular targets for therapeutic interventions.
... However, the deletion of either IL-12p19 or IL-23p35 is not adequate to prevent the development of cholangitis. 44 Therefore, targeting the upstream immune responses may be feasible for the development of possible therapeutic strategies. Antigen-presenting cells produce IL-12 in the setting of an infection. ...
... In particular, IFN-γ −/− mice showed reduced lymphocyte infiltration. 44 In addition, the number and function of Tregs were impaired in autoimmune diseases. 51,52 The lack of Treg cells resulted in CD8 + Tcell-mediated damage in IL-2Rα/CD25-deficient mice, and this finding was similar to those in patients with PBC. ...
Background
Primary biliary cholangitis (PBC), an autoimmune liver disease, presents with progressive damage to the intrahepatic bile ducts with infiltrating mononuclear cells and the appearance of anti‐mitochondrial antibodies (AMAs). The initiation of autoimmune liver disease is permissively mediated by dysfunctional regulatory T cells (Treg cells). Naïve CD4⁺ T cells cultured with splenic B220⁺ cells without additional cytokines or chemicals can differentiate into specific types of Treg cells (Treg/B cells) without expressing forkhead box P3. In this study, we explored the effects of Treg/B cells on disease severity and changes in intestinal microbiota in a murine model of PBC.
Methods
Treg/B cells were administered to 2‐octenoic acid‐induced PBC mice. Enzyme‐linked immunosorbent assay, flow cytometry and histopathological techniques were used to evaluate the severity of PBC and to assess its therapeutic effect. Diversity of the intestinal microbiota was determined using 16S rRNA sequencing. The suppressive mechanisms of Treg/B cells were investigated using the bone marrow‐derived dendritic cells (BMDCs).
Results
Treg/B‐cell treatment significantly decreased the levels of serum AMAs against pyruvate dehydrogenase complex E2, lowered the levels of serum bile acids, attenuated inflammatory cell infiltration, reduced dendritic cell activation, altered the population of T cells in the liver and alleviated liver collagen synthesis in PBC mice. In addition, the Treg/B‐cell treatment changed the faecal microbial diversity in PBC mice. Furthermore, Treg/B‐cell treatment decreased the levels of proinflammatory cytokines and expression of costimulatory molecules in BMDCs. This inhibitory effect was partially mediated by the cytotoxic T‐lymphocyte‐associated antigen 4 pathway.
Conclusion
Treatment with Treg/B cells in a murine model of PBC attenuated liver inflammation and altered the gut microbiota. Immune regulation of Treg/B cells may be a potential therapeutic strategy for treating autoimmune liver disease.
... Th17 population was decreased in the circulation and was associated with greater accumulation in the liver during PBC progression [38]. Deletion of IL-22, which was the hallmark cytokine for Th22 cells, reduced biliary injury in a PBC mouse model [39]. Herein, we found that transcription factors and cytokine productions by CD4 + Th cells were robustly increased in the peripheral blood of PBC patients, indicating the involvement of Th1, Th9, Th17, and Th22 cells in PBC. ...
Interleukin 35 (IL-35) mediates immunosuppression of T cells in autoimmune diseases. T cells play an important role in primary biliary cholangitis (PBC) with incompletely elucidated pathogenesis. Thus, we aimed to investigate the role of IL-35 regulation on T cells in PBC patients. Fifty-one PBC patients and 28 controls were enrolled in thih study. Plasma IL-35 level was measured. Purified peripheral CD4+ and CD8+ T cells were stimulated with exogenous IL-35 to investigate their functional phenotypes. IL-35-treated CD8+ T cells were cultured with human intrahepatic biliary epithelial cell line to determine the cytotoxicity of CD8+ T cells from PBC patients. Plasma IL-35 concentration was lower in PBC patients and negatively correlated with alkaline phosphatase. CD4+ T cells from PBC patients exhibited elevated transcription factor expressions and cytokine secretion, whereas CD8+ T cells produced increased cytotoxic molecules and cytokines. In vitro IL-35 stimulation suppressed the production of IL-17 and IL-22 by CD4+ T cells from PBC patients. CD8+ T cells treated with IL-35 mediated reduced target cell death in the direct contact co-culture system in PBC patients. This process was accompanied by reduced production of cytotoxic molecules and cytokines and increased expressions of immune checkpoint receptors in CD8+ T cells. Reduced circulating IL-35 might be insufficient to suppress T cell function, leading to the immune dysregulation in PBC patients.
... Moreover, Th17 cell infiltration is prominent in advanced PBC patients with intensive secretion of IL-23p19 by inflamed hepatocytes around degenerated BECs expressing IL-23R, IL-12RB2, and IFN-γ [190]. A study using a xenobiotic-induced murine model of PBC revealed that IL-17A deletion reduces the biliary injury [191]. In addition, the oxidative stress driven by hydrophobic bile acids and the related CCL20 production with resultant portal accumulation of Th17 cells contribute to disease development [78]. ...
In addition to carcinogenesis, T helper 17 (Th17) cells (a subtype of CD4 + T lymphocytes) are involved in the acute, chronic, and cirrhotic phases of liver diseases; however, their role in the development and progression of liver diseases remains unclear. It is difficult to elucidate the role of Th17 cells in liver diseases due to their dichotomous nature, i.e., plasticity in terms of pathogenic or host protective function depending on environmental and time phase factors. Moreover, insufficient depletion of Th17 cells by inhibiting the cytokines and transcription factors involved in their production causes difficulties in analyzing their specific role in vitro and in vivo murine models, partially due to complex interaction. This review summarizes the recent progress in understanding the plasticity and function of hepatic Th17 cells and type 3 cytokines.
... The destruction of biliary cells is mediated by liver-infiltrating autoreactive T cells [1,2]. It is commonly accepted that the augmented T helper (Th) 1 response, and corresponding cytokine IFN-γ response, play a significant role in PBC [3][4][5][6][7][8][9][10]. There are a significantly higher number of IFN-γ mRNApositive cells within the livers of PBC patients than in those of healthy individuals [3][4][5]. ...
... In experimental mouse models of PBC, there are significantly increased levels of Th1 cytokines, TNF-α and IFN-γ, in the liver [11][12][13]. Moreover, the deletion of IFN-γ in a PBC mouse model reduces inflammatory portal infiltrates associated with the prevention of bile duct damage [10]. ...
Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease with augmented T helper (Th) 1 and corresponding cytokine IFN-γ immune responses. Using 2-octynoic acid (2-OA) coupled to OVA (2-OA-OVA)-induced mouse models of autoimmune cholangitis (inducible chemical xenobiotic models of PBC), our previous study demonstrated that overexpression of IFN-γ in the model mice enhanced liver inflammation upon disease initiation, but subsequently led to the suppression of chronic inflammation with an increase in interleukin-30 (IL-30) levels. In this study, we investigated whether IL-30 had an immunosuppressive function and whether it could be part of an immune therapeutic regimen for PBC, by treating model mice with murine IL-30-expressing recombinant adeno-associated virus (AAV-mIL-30). We first defined the effects of AAV-mIL-30 in vivo by administering it to a well-known concanavalin A (ConA)-induced hepatitis model of mice and found that AAV-mIL-30 reduced the numbers of activated CD25+CD4+ T cells and the levels of serum IFN-γ and IL-12. In autoimmune cholangitis, decreased numbers of activated CD4+ T cells and Foxp3+ regulatory T cells were noted in the mice treated with AAV-mIL-30 at 3 weeks after the 2-OA-OVA immunization. Treatment with IL-30 did not change the features of autoimmune cholangitis including autoantibodies, cell infiltration, and collagen deposition in the liver at 11 weeks of examination. However, increased levels of cytokines and chemokines were observed. These results suggest that IL-30 suppresses not only CD4+ T cells but also regulatory T cells. Additionally, the administration of IL-30 did not suppress liver inflammation in the murine model of PBC.
... Moreover, serum levels of IL-23 and IL-17 were positively correlated with serum GGT levels (8) and immunohistochemistry studies revealed expression of IL-23p19 in portal tracts of patients with advance disease (9). Mice deficient for IL-23 in all cells were found to be protected from PBC development (10), however the mechanisms involved and the cellular source of IL-23 has not been investigated. Of note, it has been suggested that IL-23 is expressed specifically by inflamed portal hepatocytes in PBC patients (9). ...
Background and Aims
Primary Biliary Cholangitis (PBC) is an organ-specific autoimmune liver disease. Mononuclear phagocytes (MNPs), comprise of monocyte, dendritic cells and monocyte-derived macrophages, constitute major arm of the innate immune system known to be involved in the pathogenesis of autoimmune disorders. MNPs were shown to accumulate around intra-hepatic bile ducts in livers of PBC patients. Interleukin 23 (IL-23) is a pro-inflammatory cytokine. IL-23-positive cells were detected in livers of patients with advanced stage PBC and IL-23 serum levels found to be in correlation with PBC disease severity. Our overall goal was to assess the importance of IL-23 derived from MNPs in PBC pathogenesis.
Methods
We utilized an inducible murine model of PBC and took advantage of transgenic mice targeting expression of IL-23 by specific MNP populations. Analysis included liver histology assessment, flow cytometry of hepatic immune cells and hepatic cytokine profile evaluation. Specific MNPs sub-populations were sorted and assessed for IL-23 expression levels.
Results
Flow cytometry analysis of non-parenchymal liver cells in autoimmune cholangitis revealed massive infiltration of the liver by MNPs and neutrophils and a decrease in Kupffer cells numbers. In addition, a 4-fold increase in the incidence of hepatic IL-17A producing CD4⁺ T cells was found to be associated with an increase in hepatic IL23-p19 and IL17A expression levels. Disease severity was significantly ameliorated in both CD11ccreP19flox/flox and CX3CR1creP19 flox/flox mice as assessed by reduced portal inflammation and decreased hepatic expression of various inflammatory cytokines. Amelioration of disease severity was associated with reduction in IL-17A producing CD4⁺ T cells percentages and decreased hepatic IL23-p19 and IL17A expression levels. qRT-PCR analysis of sorted hepatic MNPs demonstrated high expression levels of IL-23 mRNA specifically by CX3CR1hiCD11c⁺ monocyte-derived macrophages.
Conclusion
Our results indicate a major role for IL-23 produced by hepatic monocyte-derived macrophages in the pathogenesis of PBC. These results may pave the road for the development of new immune-based and cell specific therapeutic modalities for PBC patients not responding to current therapies.
... JAKs are a family of protein tyrosine kinases (JAK1, JAK2, JAK3 and tyrosine kinase 2 [TYK2]) that play an important role in cytokine signal transduction. Baricitinib is a JAK1/2 inhibitor that demonstrates selectivity for and inhibition of JAK1 and JAK2 with lower potency towards inhibition of JAK3 or TYK2 [17]. JAKs also transduce intracellular signals from cell surface receptors for a number of cytokines and growth factors involved in hematopoiesis, inflammation and immune function [18]. ...
Background and aims
There is an unmet need for alternative treatments for patients with primary biliary cholangitis (PBC) who do not respond to treatment with ursodeoxycholic acid (UDCA). A proof-of-concept study of baricitinib, an orally administered Janus kinase 1 and 2 inhibitor, was initiated to evaluate its use in PBC patients.
Approach and results
Patients with PBC showing inadequate response or intolerance to UDCA were eligible. This was a randomized, double-blinded placebo-controlled trial. Enrollees were assigned 1:1 to baricitinib (2 mg/day) or placebo. Endpoints included change in alkaline phosphatase (ALP), itch Numeric Rating Score (NRS) and fatigue NRS at 12 weeks post-baseline; exploratory markers included high sensitivity C-reactive protein (hs-CRP) and Enhanced Liver Fibrosis (ELF) score.
Due to low enrollment, the study was terminated early. Two patients were enrolled and completed the trial; 1 was randomized to receive baricitinib and 1 to placebo. Over the treatment period, the baricitinib-treated patient demonstrated a 30% decrease in ALP and a 7-point improvement in the itch NRS, but a 2-point increase in the Fatigue NRS. Markers of inflammation and liver fibrosis (hs-CRP and ELF score) also improved over the study period. In contrast, the placebo-treated patient showed no improvement in primary or secondary endpoints. A single non-serious treatment-emergent adverse event of moderate sinusitis was reported by the baricitinib-treated patient at day 47.
Conclusions
In a 12-week trial, a patient with PBC showing inadequate response to treatment with UDCA demonstrated a dramatic response to treatment with baricitinib.
... All mice were 6-10 weeks old and were housed in pathogen-free conditions. Autoimmune cholangitis was induced using 2OA, a synthetic chemical mimic of lipoic acid-lysine located within the inner domain of the E2 subunit of the pyruvate dehydrogenase complex, coupled with BSA (2OA-BSA) as previously described [46][47][48]. As control, another group of mice was injected in parallel with 100 μL of PBS. ...
Ursodeoxycholic acid (UDCA) is the primary treatment for primary biliary cholangitis (PBC), but its mechanism of action remains unclear. Studies suggest that UDCA enhances nuclear factor erythroid 2‐related factor 2 (NFE2L2) expression and that the interaction between interferon γ (IFNγ) and C‐X3‐C motif chemokine ligand 1 (CX3CL1) facilitates biliary inflammation in PBC. Therefore, we examined the effects of UDCA on the expression of IFNγ and CX3CL1 in in vitro and in vivo PBC models such as human liver tissue, a murine model, cell lines, and isolated human intrahepatic biliary epithelial cells (IHBECs). We observed a significant decrease in IFNγ mRNA levels and positive correlations between IFNγ and CX3CL1 mRNA levels post‐UDCA treatment in PBC livers. NFE2L2‐mediated transcriptional activation was significantly enhanced in UDCA‐treated Jurkat cells. In 2‐octynoic acid‐immunized mice, IFNγ production by liver‐infiltrating T cells was dependent on NFE2L2 activation. IFNγ significantly and dose‐dependently induced CX3CL1 expression, which was significantly decreased in HuCC‐T1 cells and IHBECs upon UDCA treatment. These results suggest that UDCA‐induced suppression of IFNγ and CX3CL1 production attenuates the chemotactic and adhesive abilities of liver‐infiltrating T cells in PBC.
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... Studies have also shown that the IL-23/IL-17A signaling pathway is essential for inducing autoimmune inflammation and is involved in the PBC pathogenesis. 22,23 Therefore, the FoxP3 and IL-23/IL-17A signaling pathways may play roles in inducing autoimmunity in PBC. DFS, created by Professor Cheng Liangbin, consists of Qingdai (Indigo Naturalis) and Baifan (Alumen) (1∶8 ratio). ...
Objective:
To investigate the mechanism by which Daifan San (DFS) prevents and treats primary biliary cirrhosis (PBC) via the forkhead box P3 (FoxP3) and interleukin (IL)-23/IL-17A signaling pathways.
Methods:
Ninety C57BL/6 mice were randomly divided into the control, model, DFS low-dose, DFS middle-dose, DFS high-dose and ursodeoxycholic acid (UDCA) groups (n = 15 per group). A mouse model of PBC was induced using polyinosinic polycytidylic acids (poly I:C). Lymphocyte subset expression in the peripheral blood was analyzed via flow cytometry. The inflammatory cytokines and antimitochondrial autoantibody (AMA) levels were detected via enzyme-linked immunosorbent assays. The expressions and location of type I collagen, type III collagen, cytokeratin 19 and FoxP3 in the liver tissue were evaluated via immunohistochemistry. FoxP3, IL-23 and IL-17 expressions in the peripheral blood and liver tissue were evaluated via real-time polymerase chain reaction and western blotting.
Results:
IL-17, IL-23, IL-8, IL-33, TNF-a, and AMA expressions were significantly increased in the model group and decreased in the DFS and UDCA groups. Conversely, Treg cell and FoxP3 expressions were significantly decreased in the model group and increased in the DFS and UDCA groups. The IL-23/IL-17A signaling pathway was closely correlated with chronic inflammation of the bile duct in PBC and functional deletion of Treg cells, leading to reduced FoxP3 levels and mediating the loss of tolerance in PBC.
Conclusion:
DFS may delay the occurrence and relieve the symptoms of PBC by downregulating IL-23/IL-17A signaling pathway expression and upregulating FoxP3 expression.
