Abstract
Background and AimsPrimary 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.MethodsWe 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.ResultsFlow 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.ConclusionOur 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.
Highlights
Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease characterized by progressive destruction of the intrahepatic bile ducts, leading to cholestasis, portal inflammation, fibrosis and potentially cirrhosis and liver failure [1]
We have recently demonstrated that infiltration of Ly6Chi monocytes to the liver is crucial to the pathogenesis of PBC and inhibition of the recruitment of these cells ameliorated all aspects of the disease
In the current study we explored the importance of Interleukin 23 (IL-23) expression by mononuclear phagocytes (MNPs) for the development of experimental autoimmune cholangitis
Summary
Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease characterized by progressive destruction of the intrahepatic bile ducts, leading to cholestasis, portal inflammation, fibrosis and potentially cirrhosis and liver failure [1]. Mononuclear phagocytes (MNPs) are myeloid immune cells comprised of monocytes, macrophages (MFs) and dendritic cells (DCs). These cells are strategically positioned throughout the body tissues where they ingest and degrade dead cells, debris, and foreign material, and orchestrate inflammatory processes [2, 3]. Studies in PBC patients, demonstrated accumulation of MNPs in the liver as well as impaired function of these cells. 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. 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
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