Multi-omics approaches for drug-response characterization in primary biliary cholangitis and autoimmune hepatitis variant syndrome.

BACKGROUND: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) variant syndrome (VS) exhibit a complex overlap of AIH features with PBC, leading to poorer prognoses than those with PBC or AIH alone. The biomarkers associated with drug response and potential molecular mechanisms in this syndrome have not been fully elucidated. METHODS: Whole-transcriptome sequencing was employed to discern differentially expressed (DE) RNAs within good responders (GR) and poor responders (PR) among patients with PBC/AIH VS. Subsequent gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted for the identified DE RNAs. Plasma metabolomics was employed to delineate the metabolic profiles distinguishing PR and GR groups. The quantification of immune cell profiles and associated cytokines was achieved through flow cytometry and immunoassay technology. Uni- and multivariable logistic regression analyses were conducted to construct a predictive model for insufficient biochemical response. The performance of the model was assessed by computing the area under the receiver operating characteristic (AUC) curve, sensitivity, and specificity. FINDINGS: The analysis identified 224 differentially expressed (DE) mRNAs, 189 DE long non-coding RNAs, 39 DE circular RNAs, and 63 DE microRNAs. Functional pathway analysis revealed enrichment in lipid metabolic pathways and immune response. Metabolomics disclosed dysregulated lipid metabolism and identified PC (18:2/18:2) and PC (16:0/20:3) as predictors. CD4+ T helper (Th) cells, including Th2 cells and regulatory T cells (Tregs), were upregulated in the GR group. Pro-inflammatory cytokines (IFN-γ, TNF-α, IL-9, and IL-17) were downregulated in the GR group, while anti-inflammatory cytokines (IL-10, IL-4, IL-5, and IL-22) were elevated. Regulatory networks were constructed, identifying CACNA1H and ACAA1 as target genes. A predictive model based on these indicators demonstrated an AUC of 0.986 in the primary cohort and an AUC of 0.940 in the validation cohort for predicting complete biochemical response. CONCLUSION: A combined model integrating genomic, metabolic, and cytokinomic features demonstrated high accuracy in predicting insufficient biochemical response in patients with PBC/AIH VS. Early recognition of individuals at elevated risk for insufficient response allows for the prompt initiation of additional treatments.

Engaging natural regulatory myeloid cells to restrict T-cell hyperactivation-induced liver inflammation via extracellular vesicle-mediated purine metabolism regulation.

Rationale: Dysregulated T-cell immune response-mediated inflammation plays critical roles in the pathology of diverse liver diseases, but the underlying mechanism of liver immune homeostasis control and the specific therapies for limiting T-cell overactivation remain unclear. Methods: The metabolic changes in concanavalin A (ConA) mice and autoimmune hepatitis (AIH) patients and their associations with liver injury were analyzed. The expression of purine catabolism nucleases (e.g., CD39 and CD73) on liver cells and immune cells was assessed. The effects of MCregs and their extracellular vesicles (EVs) on CD4+ T-cell overactivation and the underlying mechanism were also explored. Results: Our findings revealed significant alterations in purine metabolism in ConA mice and AIH patients, which correlated with liver injury severity and therapeutic response. CD39 and CD73 were markedly upregulated on CD11b+Gr-1+ MCs under liver injury conditions. The naturally expanded CD39+CD73+Gr-1highCD11b+ MCreg subset during early liver injury effectively suppressed CD4+ T-cell hyperactivation and liver injury both in vitro and in vivo. Mechanistically, MCregs released CD73high EVs, which converted extracellular AMP to immunosuppressive metabolites (e.g., adenosine and inosine), activating the cAMP pathway and inhibiting glycolysis and cytokine secretion in activated CD4+ T cells. Conclusions: This study provides insights into the mechanism controlling immune homeostasis during the early liver injury phase and highlights that MCreg or MCreg-EV therapy may be a specific strategy for preventing diverse liver diseases induced by T-cell overactivation.

Metabolic Reprogramming of CD4+ T Cells by Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuates Autoimmune Hepatitis Through Mitochondrial Protein Transfer.

Background: Autoimmune hepatitis (AIH) is a serious liver disease characterized by immune disorders, particularly effector T-cell overactivation. This study aimed to explore the therapeutic effect and underlying mechanism of mesenchymal stem cell-derived extracellular vesicle (MSC-EV) treatment on CD4+ T-cell overactivation and liver injury in AIH. Methods: The metabolic changes of CD4+ T cells were assayed in human AIH and mouse hepatitis models. The liver protective effect of MSC-EVs was evaluated by transaminase levels, liver histopathology and inflammation. The effect of MSC-EVs on the metabolic state of CD4+ T cells was also explored. Results: Enhanced glycolysis (eg, ~1.5-fold increase in hexokinase 2 levels) was detected in the CD4+ T cells of AIH patient samples and mouse hepatitis models, whereas the inhibition of glycolysis decreased CD4+ T-cell activation (~1.8-fold decrease in CD69 levels) and AIH liver injury (~6-fold decrease in aminotransferase levels). MSC-EV treatment reduced CD4+ T-cell activation (~1.5-fold decrease in CD69 levels) and cytokine release (~5-fold decrease in IFN-γ levels) by reducing glycolysis (~3-fold decrease) while enhancing mitochondrial oxidative phosphorylation (~2-fold increase in maximal respiration) in such cells. The degree of liver damage in AIH mice was ameliorated after MSC-EV treatment (~5-fold decrease in aminotransferase levels). MSC-EVs carried abundant mitochondrial proteins and might transfer them to metabolically reprogram CD4+ T cells, whereas disrupting mitochondrial transfer impaired the therapeutic potency of MSC-EVs in activated CD4+ T cells. Conclusion: Disordered glucose metabolism promotes CD4+ T-cell activation and associated inflammatory liver injury in AIH models, which can be reversed by MSC-EV therapy, and this effect is at least partially dependent on EV-mediated mitochondrial protein transfer between cells. This study highlights that MSC-EV therapy may represent a new avenue for treating autoimmune diseases such as AIH.

Examining the Nonlinear and Synergistic Effects of Multidimensional Elements on Commuting Carbon Emissions: A Case Study in Wuhan, China.

Understanding the specific effects of multidimensional elements of a built environment, transportation management policies, and the socio-demographics of travelers associated with commuting carbon emissions is significant for planners in promoting low-carbon and healthy urban development through transportation and land use and urban management policies. Most of the existing studies focus on the complex mechanisms affecting commuting behavior, but the relevant elements and specific mechanisms affecting commuting carbon emissions have not received sufficient attention. This study uses a random forest approach to analyze residential travel data from Wuhan, China. The results show that built environment and transportation demand management policies are critical to commuting carbon emissions, and that there is a non-linear association between multidimensional factors and commuting carbon emissions in Chinese cities. In addition, the study examines the synergistic effects of built environment and transportation management policies on commuting carbon emissions among different built environment elements. The results of the study provide valuable insights for planners in formulating low-carbon city and transportation development policies.

Pathogenic and Potential Therapeutic Roles of Exosomes Derived From Immune Cells in Liver Diseases.

Liver diseases, such as viral hepatitis, alcoholic hepatitis and cirrhosis, nonalcoholic steatohepatitis, and hepatocellular carcinoma place a heavy burden on many patients worldwide. However, the treatment of many liver diseases is currently insufficient, and the treatment may be associated with strong side effects. Therapies for liver diseases targeting the molecular and cellular levels that minimize adverse reactions and maximize therapeutic effects are in high demand. Immune cells are intimately involved in the occurrence, development, and prognosis of liver diseases. The immune response in the liver can be suppressed, leading to tolerance in homeostasis. When infection or tissue damage occurs, immunity in the liver is activated rapidly. As small membrane vesicles derived from diverse cells, exosomes carry multiple cargoes to exert their regulatory effects on recipient cells under physiological or pathological conditions. Exosomes from different immune cells exert different effects on liver diseases. This review describes the biology of exosomes and focuses on the effects of exosomes from different immune cells on pathogenesis, diagnosis, and prognosis and their therapeutic potential in liver diseases.

Metabolic heterogeneity caused by HLA-DRB1*04:05 and protective effect of inosine on autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an autoimmune disease caused by disruption of liver immune homeostasis. Genetic studies have revealed the predisposition of AIH with the human leukocyte antigen (HLA) region. Recently, metabolomics integrated with genomics has identified many genetic loci of biomedical interest. However, there is no related report in AIH. In the present study, we found that HLA-DRB1*04:05 was linked to the clinical features and prognosis of AIH in Chinese patients. Furthermore, our patients were divided into DRB1*04:05 positive and DRB1*04:05 negative groups and the metabolic profiling was done by HPLC/MS. We chose inosine, one of the highly altered metabolites, to explore the effect on an acute severe hepatitis murine model. The results showed that inosine treatment attenuated hepatocyte apoptosis, enhanced antioxidant ability and inhibited the activation and glycolysis of CD4+ T cell. We propose that inosine participates in the regulation of AIH through its protective effect on hepatocytes and inhibition of overactivated immune cells, which might provide a potential novel approach in treating acute form of AIH.