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Nature. 2019 Feb;566(7743):249-253. doi: 10.1038/s41586-019-0899-7. Epub 2019 Jan 30.

Interleukin-22 protects intestinal stem cells against genotoxic stress.

Gronke K1,2,3,4,5,6, Hernández PP5,6,7, Zimmermann J5, Klose CSN1,5,8, Kofoed-Branzk M1,2,3,4,5,6, Guendel F1,2,3,4,5, Witkowski M1,2,3,4, Tizian C1,2,3,4, Amann L5,9, Schumacher F10,11, Glatt H12,13, Triantafyllopoulou A14,15, Diefenbach A16,17,18,19,20.

Author information

1
Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
2
Berlin Institute of Health (BIH), Berlin, Germany.
3
Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Berlin, Germany.
4
Department of Medical Microbiology and Hygiene, University Medical Centre, University of Mainz, Mainz, Germany.
5
Department of Medical Microbiology, University of Freiburg, Freiburg, Germany.
6
Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.
7
Macrophages and Development of Immunity, Institute Pasteur, Paris, France.
8
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
9
Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.
10
Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
11
Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
12
German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Potsdam, Germany.
13
Department Food Safety, Federal Institute for Risk Assessment, Berlin, Germany.
14
Department of Rheumatology and Clinical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
15
Innate Immunity in Rheumatic Diseases, Deutsches Rheuma-Forschungszentrum, Berlin, Germany.
16
Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany. andreas.diefenbach@charite.de.
17
Berlin Institute of Health (BIH), Berlin, Germany. andreas.diefenbach@charite.de.
18
Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Berlin, Germany. andreas.diefenbach@charite.de.
19
Department of Medical Microbiology and Hygiene, University Medical Centre, University of Mainz, Mainz, Germany. andreas.diefenbach@charite.de.
20
Department of Medical Microbiology, University of Freiburg, Freiburg, Germany. andreas.diefenbach@charite.de.

Abstract

Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1-3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.

PMID:
30700914
DOI:
10.1038/s41586-019-0899-7

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