Interleukin-22 protects intestinal stem cells against genotoxic stress

Gronke, Konrad; Hernández, Pedro P.; Zimmermann, Jakob; Klose, Christoph S. N.; Kofoed-Branzk, Michael; Guendel, Fabian; Witkowski, Mario; Tizian, Caroline; Amann, Lukas; Schumacher, Fabian; Glatt, Hansruedi; Triantafyllopoulou, Antigoni; Diefenbach, Andreas (2019). Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature, 566(7743), pp. 249-253. Macmillan Journals Ltd. 10.1038/s41586-019-0899-7

Preview	Text emss-81063.pdf - Accepted Version Available under License Publisher holds Copyright. Download (5MB) | Preview
	Text Nature 2019 Gronke.pdf - Published Version Restricted to registered users only Available under License Publisher holds Copyright. Download (62MB)

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.

Interest & Impact

Downloads

1754 since deposited on 17 Jun 2020
365 in the past 12 months

Citations

5 Citations in Web of Science ®
6 Citations in Scopus

Search

in Google Scholar™

Services

Actions (login required)

Edit item

Actions (login required)

Edit item