EN
Project - B01:
Intestinal inflammation modulates liver immune responses
Project leaders:
Prof. Dr. med. Samuel Huber &
Dr. med. Jan Kempski
Summary
There is a close anatomical connection between the liver and the intestine. This connection is further highlighted by the clinical association between Primary Sclerosing Cholangitis (PSC) and Inflammatory Bowel Disease (IBD). Interestingly, our clinical and experimental data suggest that intestinal inflammation is not only associated with but can also modulate the disease course of PSC. We found that the hepatic inflammation of Mdr2-deficient mice (a murine model of sclerosing cholangitis) was reduced when colitis was induced in those mice. Moreover, our preliminary data indicate that pro- and anti-inflammatory lymphocytes migrate from the inflamed colon into the liver. Based on the preliminary data, our central hypothesis is that intestinal inflammation can modulate hepatic immune responses via the migration of T and B cells and via changes in the intestinal microbiota. We aim to test this hypothesis by studying the role of T and B cell migration between the gut and the liver in murine sclerosing cholangitis and colitis models. Also, we will perform single-cell RNA and TCR/BCR sequencing of immune cells from the intestines and livers of people with PSC and PSC-IBD to identify which T and B cell clonotypes are shared between those organs. Moreover, we aim to identify factors driving the migration of protective and pathogenic lymphocytes from the gut into the liver and test their functional role using knock out models of chemokines or chemokine receptors. Finally, we will study whether the microbial changes observed in PSC, PSC-IBD and IBD without PSC play a role in regulating immune cell composition, migration and modulating hepatic immune responses in PSC. To this end, we will use patient-specific gnotobiotic mice by engrafting germ-free Mdr2-deficient mice with faecal microbiota from people with PSC, PSC-IBD, IBD and from healthy controls or from mouse models of the respective diseases. We will use those mice to assess the functional role of the microbiota in influencing the migration of lymphocytes between the intestine and the liver and the disease course of sclerosing cholangitis.
The co-occurrence of PSC and IBD highlights the importance of the immunological cross-talk between the intestine and the liver to modulate hepatic immune regulation. Our long-term aim is to understand the mechanisms regulating those interactions to pave the way for new therapies for inflammatory liver diseases.
Project plan
There is a known clinical association between PSC and IBD. However, it remains unclear how IBD influences the development of liver pathology in PSC. Our preliminary data indicate that intestinal inflammation can have both protective and pathogenic effects on liver pathology in mouse models of sclerosing cholangitis and colitis. In the first funding period, we aim to decipher the molecular and cellular mechanisms mediating the protective and pathogenic effects of IBD on PSC as a model system for the gut-liver axis. Our central hypothesis is that intestinal inflammation can modulate hepatic immune responsesvia the migration of immune cells to the liver induced by changes in the intestinal microbiota. Our long-term aim is the identification of mechanisms linking the intestine with hepatic immune regulation in order to build the basis for new therapies targeting inflammatory diseases.
In order to test this hypothesis, our work programme has the following work packages (WP):
WP1: To decipher the role of T cell migration between the intestine and the liver in regulating hepatic immune responses.
WP2: To decipher the role of B cell migration between the intestine and the liver in regulating hepatic immune responses.
WP3: To analyse the role of the intestinal microbiota in regulating the T and B cell composition and migration as well as in modulating hepatic immune responses.
Project related publications
Stumme F, Steffens N, Steglich B, Mathies F, Nawrocki M, Sabihi M, Soukou-Wargalla S, Göke E, Kempski J, Fründt T, Weidemann S, Schramm C, Gagliani N, Huber S, Bedke T. A protective effect of inflammatory bowel disease on the severity of sclerosing cholangitis. Front Immunol 2024;15:1307297. doi: 10.3389/fimmu.2024.1307297. Open access
Mathies F#, Steffens N#, Kleinschmidt D, Stuhlmann F, Huber FJ, Roy U, Meyer T, Luetgehetmann M, von Petersdorff M, Seiz O, Herkel J, Schramm C, Flavell RA, Gagliani N, Krebs C, Panzer U, Abdullah Z, Strowig T, Bedke T, Huber S. Colitis Promotes a Pathological Condition of the Liver in the Absence of Foxp3+ Regulatory T Cells. J Immunol 2018;201:3558-3568. doi: 10.4049/jimmunol.1800711.
Poch T#, Krause J#, Casar C, Liwinski T, Glau L, Kaufmann M, Ahrenstorf AE, Hess LU, Ziegler AE, Martrus G, Lunemann S, Sebode M, Li J, Schwinge D, Krebs CF, Franke A, Friese MA, Oldhafer KJ, Fischer L, Altfeld M, Lohse AW, Huber S, Tolosa E, Gagliani N, Schramm C. Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis. J Hepatol 2021;75:414-423. doi: 10.1016/j.jhep.2021.03.016. Open access
Giannou AD#, Kempski J#, Shiri AM#, Lücke J, Zhang T, Zhao L, Zazara DE, Cortesi F, Riecken K, Amezcua Vesely MC, Low JS, Xu H, Kaffe E, Garcia-Perez L, Agalioti T, Yamada Y, Jungraithmayr W, Zigmond E, Karstens KF, Steglich B, Wagner J, Konczalla L, Carambia A, Schulze K, von Felden J, May P, Briukhovetska D, Bedke T, Brockmann L, Starzonek S, Lange T, Koch C, Riethdorf S, Pelczar P, Böttcher M, Sabihi M, Huber FJ, Reeh M, Grass JK, Wahib R, Seese H, Stüben BO, Fard-Aghaie M, Duprée A, Scognamiglio P, Plitzko G, Meiners J, Soukou S, Wittek A, Manthey C, Maroulis IC, Arck PC, Perez D, Gao B, Zarogiannis SG, Strowig T, Pasqualini R, Arap W, Gosálvez JS, Kobold S, Prinz I, Guse AH, Tachezy M, Ghadban T, Heumann A, Li J, Melling N, Mann O, Izbicki JR, Pantel K, Schumacher U, Lohse AW, Flavell RA, Gagliani N, Huber S. Tissue resident iNKT17 cells facilitate cancer cell extravasation in liver metastasis via interleukin-22. Immunity 2023;56:125-142.e12. doi: 10.1016/j.immuni.2022.12.014. Open access.
Kempski J#, Giannou AD#, Riecken K, Zhao L, Steglich B, Lücke J, Garcia-Perez L, Karstens KF, Wöstemeier A, Nawrocki M, Pelczar P, Witkowski M, Nilsson S, Konczalla L, Shiri AM, Kempska J, Wahib R, Brockmann L, Huber P, Gnirck AC, Turner JE, Zazara DE, Arck PC, Stein A, Simon R, Daubmann A, Meiners J, Perez D, Strowig T, Koni P, Kruglov AA, Sauter G, Izbicki JR, Guse AH, Rösch T, Lohse AW, Flavell RA, Gagliani N#, Huber S#. IL22BP Mediates the Antitumour Effects of Lymphotoxin Against Colorectal Tumours in Mice and Humans. Gastroenterology 2020;159:1417-1430.e3 doi: 10.1053/j.gastro.2020.06.033. Open access.
Kleinschmidt D, Giannou AD, McGee HM, Kempski J, Steglich B, Huber FJ, Ernst TM, Shiri AM, Wegscheid C, Tasika E, Hübener P, Huber P, Bedke T, Steffens N, Agalioti T, Fuchs T, Noll J, Lotter H, Tiegs G, Lohse AW, Axelrod JH, Galun E, Flavell RA, Gagliani N, Huber S. A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury. J Immunol 2017;199:4078-4090. doi: 10.4049/jimmunol.1700587.
Brockmann L, Soukou S, Steglich B, Czarnewski P, Zhao L, Wende S, Bedke T, Ergen C, Manthey C, Agalioti T, Geffken M, Seiz O, Parigi SM, Sorini C, Geginat J, Fujio K, Jacobs T, Roesch T, Izbicki JR, Lohse AW, Flavell RA, Krebs C, Gustafsson JA, Antonson P, Roncarolo MG, Villablanca EJ, Gagliani N, Huber S. Molecular and functional heterogeneity of IL-10-producing CD4+ T cells. Nat Commun 2018;9:5457. doi: 10.1038/s41467-018-07581-4. Open access.
Perez LG, Kempski J, McGee HM, Pelzcar P, Agalioti T, Giannou A, Konczalla L, Brockmann L, Wahib R, Xu H, Vesely MCA, Soukou S, Steglich B, Bedke T, Manthey C, Seiz O, Diercks BP, Gnafakis S, Guse AH, Perez D, Izbicki JR, Gagliani N, Flavell RA, Huber S. TGF-β signalling in Th17 cells promotes IL-22 production and colitis-associated colon cancer. Nat Commun 2020;11:2608. doi: 10.1038/s41467-020-16363-w. Open access.
Karstens KF, Kempski J, Giannou AD, Pelczar P, Steglich B, Steurer S, Freiwald E, Woestemeier A, Konczalla L, Tachezy M, Reeh M, Bockhorn M, Perez D, Mann O, Lohse AW, Roesch T, Izbicki JR, Gagliani N#, Huber S#. Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival. Cancer Immunol Immunother 2020;69:1043-1056. doi: 10.1007/s00262-020-02517-8. Open access.
Pelczar P#, Witkowski M#, Perez LG#, Kempski J, Hammel AG, Brockmann L, Kleinschmidt D, Wende S, Haueis C, Bedke T, Witkowski M, Krasemann S, Steurer S, Booth CJ, Busch P, König A, Rauch U, Benten D, Izbicki JR, Rösch T, Lohse AW, Strowig T, Gagliani N, Flavell RA#, Huber S#. A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science 2016;354:358-362. doi: 10.1126/science.aah5903.
# equally contributing authors