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 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.
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RNA-seq data are available at ArrayExpress (http://www.ebi.ac.uk/arrayexpress/) under accession number E-MTAB-6723. All datasets generated and/or analysed during the current study are presented in this published article, the accompanying Source Data or Supplementary Information files, or are available from the corresponding author upon reasonable request.
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We thank M. Di Virgilio, B. Epe, T. Nikolova, J. Ommer and the members of the Diefenbach laboratory for valuable discussions; K. Oberle for technical assistance; the IMB Flow Cytometry Core Facility (J. Hartwig, I. Schäfer and S. Möckel); the IMB Microscopy Core Facility (S. Ritz and J. Schwirz); the Deep Sequencing Facility at the MPI Immunobiology & Epigenetics Freiburg; and EUCOMM for providing targeted ES cells. The work was supported by the European Research Council (ERC StG No. 311377 to A.D.), the European Union’s Horizon 2020 programme (Marie Skłodowska-Curie Grant Agreement No. 744257 to J.Z.), Deutsche Forschungsgemeinschaft (TR-SFB156/A02, TR-SFB241/A01, SPP1937-DI764/9 to A.D. and KL2963/1-1 to C.S.N.K.), Einstein Foundation Berlin (Einstein Professorship to A.D.), the German Rheumatism Research Centre (to A.D. and A.T.) and the Max-Planck Society (IMPRS-MCB, MPI Freiburg to K.G., M.K.-B. and P.P.H.).
Nature thanks R. Locksley, W. Ouyang and the other anonymous reviewer(s) for their contribution to the peer review of this work.