Interleukin-22 protects intestinal stem cells against genotoxic stress

  • 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 development1,2,3. 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 carcinogensEnvironmental 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 development1,2,3. 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.show moreshow less

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Author details:Konrad GronkeGND, Pedro P. Hernandez, Jakob ZimmermannORCiD, Christoph S. N. Klose, Michael Kofoed-Branzk, Fabian Guendel, Mario Witkowski, Caroline Tizian, Lukas Amann, Fabian SchumacherORCiDGND, Hansruedi Glatt, Antigoni Triantafyllopoulou, Andreas DiefenbachORCiD
DOI:https://doi.org/10.1038/s41586-019-0899-7
ISSN:0028-0836
ISSN:1476-4687
Pubmed ID:http://www.ncbi.nlm.nih.gov/pubmed?term=30700914
Title of parent work (English):Nature : the international weekly journal of science
Publisher:Nature Publ. Group
Place of publishing:London
Publication type:Article
Language:English
Date of first publication:2019/01/30
Completion year:2019
Release date:2021/04/07
Volume:566
Issue:7743
Page number:24
First page:249
Last Page:253
Funding institution:European Research Council (ERC StG)European Research Council (ERC) [311377]; European UnionEuropean Union (EU) [744257]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [TR-SFB156/A02, TR-SFB241/A01, SPP1937-DI764/9, KL2963/1-1]; Einstein Foundation Berlin (Einstein Professorship); German Rheumatism Research Centre; Max-Planck Society (IMPRS-MCB, MPI Freiburg)
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
DDC classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit