Monocytes as potential mediators of pathogen-induced Th17 differentiation in patients with primary sclerosing cholangitis (PSC)

TY - JOUR

T1 - Monocytes as potential mediators of pathogen-induced Th17 differentiation in patients with primary sclerosing cholangitis (PSC)

AU - Kunzmann, Lilly Kristin

AU - Schoknecht, Tanja

AU - Poch, Tobias

AU - Henze, Lara

AU - Stein, Stephanie

AU - Kriz, Marvin

AU - Grewe, Ilka

AU - Preti, Max

AU - Hartl, Johannes

AU - Pannicke, Nadine

AU - Peiseler, Moritz

AU - Sebode, Marcial

AU - Zenouzi, Roman

AU - Horvatits, Thomas

AU - Böttcher, Marius

AU - Petersen, Britt-Sabina

AU - Weiler-Normann, Christina

AU - Hess, Leonard U

AU - Ahrenstorf, Annika Elise

AU - Lunemann, Sebastian

AU - Martrus, Gloria

AU - Fischer, Lutz

AU - Li, Jun

AU - Carambia, Antonella

AU - Kluwe, Johannes

AU - Huber, Samuel

AU - Lohse, Ansgar W

AU - Franke, Andre

AU - Herkel, Johannes

AU - Schramm, Christoph

AU - Schwinge, Dorothee

N1 - © 2020 by the American Association for the Study of Liver Diseases.

PY - 2020/1/23

Y1 - 2020/1/23

N2 - T cells from patients with primary sclerosing cholangitis (PSC) show a prominent IL-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant 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 towards Th17. Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using trans-well experiments with cholangiocytes. Cytokine production was measured using flow cytometry, ELISA, RNA in situ hybridization and quantitative real time PCR. Genetic polymorphisms were obtained from Immunochip analysis. Following ex vivo stimulation with PMA/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 CCL-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14hi CD16int and CD14lo CD16hi monocytes/macrophages were increased compared to alcoholic cirrhosis and monocytes were found to be located around bile ducts. Conclusion: 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.

AB - T cells from patients with primary sclerosing cholangitis (PSC) show a prominent IL-17 response upon stimulation with bacteria or fungi, yet the reasons for this dominant 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 towards Th17. Monocytes and T cells from blood and livers of PSC patients and controls were analyzed ex vivo and in vitro using trans-well experiments with cholangiocytes. Cytokine production was measured using flow cytometry, ELISA, RNA in situ hybridization and quantitative real time PCR. Genetic polymorphisms were obtained from Immunochip analysis. Following ex vivo stimulation with PMA/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 CCL-20 and CCL-2 in human primary cholangiocytes. In livers of patients with PSC cirrhosis, CD14hi CD16int and CD14lo CD16hi monocytes/macrophages were increased compared to alcoholic cirrhosis and monocytes were found to be located around bile ducts. Conclusion: 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.

U2 - 10.1002/hep.31140

DO - 10.1002/hep.31140

M3 - SCORING: Journal article

C2 - 31975436

VL - 72

SP - 1310

EP - 1326

JO - HEPATOLOGY

JF - HEPATOLOGY

SN - 0270-9139

IS - 4

ER -