Related Experiment Video
Updated: Oct 21, 2025
Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice
Published on: March 10, 2017
Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary
Debby Reuveni1,2, Miriam R Brezis1,2, Eli Brazowski2,3
1The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
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.
Insights
Interleukin-23 (IL-23) from liver macrophages drives Primary Biliary Cholangitis (PBC) pathogenesis. Targeting this IL-23 pathway may offer new treatments for PBC patients.
Area of Science:
- Immunology
- Hepatology
- Autoimmune Diseases
Background:
- Primary Biliary Cholangitis (PBC) is an autoimmune liver disease.
- Mononuclear phagocytes (MNPs) are implicated in autoimmune disease pathogenesis.
- IL-23 is a pro-inflammatory cytokine linked to PBC severity.
Purpose of the Study:
- To assess the role of IL-23 derived from MNPs in PBC pathogenesis.
- To investigate the therapeutic potential of targeting IL-23 in PBC.
Main Methods:
- Utilized an inducible murine model of PBC.
- Employed transgenic mice to target IL-23 expression in specific MNP populations.
- Conducted liver histology, flow cytometry, and cytokine profiling.
Main Results:
- Massive MNP and neutrophil infiltration observed in PBC livers.
- Increased IL-17A-producing CD4+ T cells correlated with elevated IL-23 and IL-17A.
- Targeting IL-23 in MNP populations ameliorated PBC severity and inflammation.
- CX3CR1hiCD11c+ monocyte-derived macrophages highly expressed IL-23 mRNA.
Conclusions:
- Hepatic IL-23 from monocyte-derived macrophages plays a key role in PBC pathogenesis.
- These findings suggest potential for novel, cell-specific therapies for PBC.
