Monocytes as Potential Mediators of Pathogen‐Induced T‐Helper 17 Differentiation in Patients With Primary Sclerosing Cholangitis (PSC)

Abstract

BaCKgRoUND aND aIMS: T cells from patients with primary sclerosing cholangitis (PSC) show a prominent interleukin (IL)-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant T-helper 17 (Th17) response in PSC are not clear. Here, we analyzed the potential role of monocytes in microbial recognition and in skewing the T-cell response toward Th17. appRoaCH aND ReSUltS: Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using transwell experiments with cholangiocytes. Cytokine production was measured using flow cytometry, enzyme-linked immunosorbent assay, RNA in situ hybridization, and quantitative real-time PCR. Genetic polymorphisms were obtained from ImmunoChip analysis. Following ex vivo stimulation with phorbol myristate acetate/ ionomycin, PSC patients showed significantly increased numbers of IL-17A-producing peripheral blood CD4 + T cells compared to PBC patients and healthy controls, indicating increased Th17 differentiation in vivo. Upon stimulation with microbes, monocytes from PSC patients produced significantly more IL-1β and IL-6, cytokines known to drive Th17 cell differentiation. Moreover, microbe-activated monocytes induced the secretion of Th17 and monocyte-recruiting chemokines chemokine (C-C motif) ligand (CCL)-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14 hi CD16 int and CD14 lo CD16 hi monocytes/ macrophages were increased compared to alcoholic cirrhosis, and monocytes were found to be located around bile ducts. CoNClUSIoNS: PSC patients show increased Th17 differentiation already in vivo. Microbe-stimulated monocytes drive Th17 differentiation in vitro and induce cholangiocytes to produce chemokines mediating recruitment of Th17 cells and more monocytes into portal tracts. Taken together, these results point to a pathogenic role of monocytes in patients with PSC. (Hepatology 2020;72:1310-1326). P rimary sclerosing cholangitis (PSC) is a chronic liver disease characterized by inflammation and fibrosis of the intra-and extrahepatic bile ducts,

Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis

“…P-values of <0.05 were considered statistically significant. The potential impact of co-variables such as sex, associated IBD, as well as stage of PSC on the data presented was examined and found to have no significant effect on our data, which is in line with previous studies [10,45]. Data is provided within respective Supplementary Figures.…”

Associations of neopterin and kynurenine–tryptophan ratio with survival in primary sclerosing cholangitis

“…IFNc concentration was also increased in PSC bile, [19] increased IFNc mRNA expression has been found in PSC explants, [20] and more IFNc-producing T cells were found in colons of ulcerative colitis patients with concomitant PSC compared with ulcerative colitis patients without PSC [21]. Furthermore, the main source of neopterin is macrophages, and the results would fit with the observation of increased numbers of macrophages in PSC livers and accumulation of macrophages in the peribiliary areas of the liver [5,[22][23][24]. Overall, there is therefore strong reason to believe that IFNc-driven inflammation with subsequent increased neopterin and KTratio occurs in PSC.…”

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression

“…We previously reported that IL-17 + cells localized around the bile ducts of PSC livers 19 . Pathogen-induced Th17 differentiation was increased in PSC patients and we recently observed that an increased Th17 differentiation in PSC already occurs in vivo 21 . The presence of IL-17-producing cells has been associated with a more severe disease phenotype and a harmful role in autoimmune liver diseases 11,[36][37][38] .…”

“…In addition, we recently reported that the monocyte-cholangiocytes interaction contributes to microbiota-induced Th17 differentiation in PSC patients 21 . Not only Th17 cells, but also IL-17 + CD8 + T (Tc17) cells were reported to accumulate in inflammatory and autoimmune liver diseases 11,22,23 .…”