Interleukin 23 Produced by Hepatic Monocyte-Derived Macrophages Is Essential for the Development of Murine Primary Biliary Cholangitis

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.

Comparison of Inflammatory Cytokine Levels in Hepatic and Jugular Veins of Patients with Cirrhosis

“…IL-23 was significantly higher (hepatic blood, p ¼ 0:04) in patients with decompensated cirrhosis. This is an interesting finding because IL-23 can be produced by hepatic monocyte-derived macrophages, corroborating that myeloid cells fuel systemic inflammation in decompensated cirrhosis [21,35,36].…”

Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression

“…Hepatic macrophages have been implicated in the pathogenesis of murine autoimmune cholangitis [ 45 ]. Macrophages were affected by the JAK1 selective kinase inhibitor and pan-JAK inhibitor tofacitinib in an experimental colitis model [ 46 ].…”

IL23R as an indicator of immune infiltration and poor prognosis in intrahepatic cholangiocarcinoma: a bioinformatics analysis

“…At present, little is known concerning the functional mechanism of IL23R in the development of CHOL. However, it was reported that IL-23 produced by macrophages derived from liver monocytes plays a major role in the pathogenesis of primary biliary cirrhosis ( 44 ), which is one of the main risk factors of CHOL ( 45 ). These and similar findings point to productive research directions in CHOL, especially related to the PI3K-Akt signaling pathway, immune-related TME, and amino acid metabolism.…”