Monocytes as Potential Mediators of Pathogen‐Induced T‐Helper 17 Differentiation in Patients With Primary Sclerosing Cholangitis (PSC)
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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 e x 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.
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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.
“Interestingly, 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.222”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [222]
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Mucosal immunity in primary sclerosing cholangitis: from the bowel to bile ducts and back again
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Gut Microbiota in Primary Sclerosing Cholangitis: From Prognostic Role to Therapeutic Implications
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Primary sclerosing cholangitis and the path to translation
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Faecal Cytolysin is Associated With Worse Survival in Patients With Primary Sclerosing Cholangitis
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Self-citationHuman Th17- and IgG3-associated autoimmunity induced by a translocating gut pathobiontPreprint
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Self-citation
- Authors
- Kunzmann, L. K., Schoknecht, T., Poch, T., Henze, L., Stein, S., Kriz, M., Grewe, I., Preti, M., Hartl, J., Pannicke, N., Peiseler, M., Sebode, M., Zenouzi, R., Horvatits, T., Böttcher, M., Petersen, B., Weiler‐Normann, C., Hess, L. U., Ahrenstorf, A. E., Lunemann, S., Martrus, G., Fischer, L., Li, J., Carambia, A., Kluwe, J., Huber, S., Lohse, A. W., Franke, A., Herkel, J., Schramm, C., & Schwinge, D.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Leibniz Institute of Virology (LIV) (DE)
- Leibniz Institute for Experimental Virology,Heinrich Pette Institute,Hamburg,Germany
- Institute of Clinical Molecular Biology,Christian‐Albrechts‐University of Kiel,Kiel,Germany
- Corresponding author
- Schramm, Christoph
- Schwinge, Dorothee
- ORCID
- Poch, Tobias
- Henze, Lara
- Stein, Stephanie
- Kriz, Marvin
- Grewe, Ilka
- Preti, Max
- Hartl, Johannes
- Peiseler, Moritz
- Sebode, Marcial
- Zenouzi, Roman
- Horvatits, Thomas
- Böttcher, Marius
- Weiler‐Normann, Christina
- Fischer, Lutz
- Li, Jun
- Carambia, Antonella
- Kluwe, Johannes
- Huber, Samuel
- Lohse, Ansgar W.
- Herkel, Johannes
- Schramm, Christoph
- Schwinge, Dorothee
- Venue
- Hepatology
- Published
- 2020-10
- Volume
- 72
- Issue
- 4
- Pages
- 1310-1326
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- OpenAlex
- W3001966225
- Cited by
- 93
- References
- 56
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 20 · 2023: 16 · 2022: 17 · 2021: 8 · 2020: 5
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Multimedialen Archiv und Publikationsserver der Christian-Albrechts-Universität zu Kiel (Christian-Albrechts-Universität zu Kiel) (publishedVersion, cc-by-nc)
- Funders
- Hamburgischen Stiftung für Wissenschaften, Entwicklung und Kultur Helmut und Hannelore Greve
- Deutsche Forschungsgemeinschaft
- Universiteit van Amsterdam
- Tufts University School of Medicine
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- primary sclerosing cholangitis, monocytes, Th17 cell differentiation, IL-17, IL-1β, interleukin-6, cholangiocytes, CCL20, MCP-1, chemokine recruitment, CD14+CD16+ monocytes, liver cirrhosis, pathogen recognition, T cell response
- MeSH terms
- Interleukin-21, Adolescent, Adult, Aged, Aged, 80 and over, Cell Differentiation, Female, Humans, Interleukins, Liver Cirrhosis, Male, Middle Aged, Monocytes, Cholangitis, Sclerosing, Chemokines, CARD Signaling Adaptor Proteins, Interleukin-1beta, Young Adult, Th17 Cells
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