A new report in Nature shows that IL-22 produced by tissue-resident innate lymphocytes in response to environmental stimuli protects intestinal stem cells (ISCs) against genotoxic stress and mutations through regulation of their DNA damage response (DDR) machinery.
To prevent malignant transformation and tumour development following exposure to genotoxins, ISCs maintain integrity of their genome via the DDR, which results in DNA repair or apoptosis. Previous studies had indicated a role for IL-22 in intestinal carcinogenesis, albeit with conflicting findings. A new paper by Konrad Gronke and colleagues set out to elucidate the pathways and effects of IL-22 signalling on carcinogenesis via stem cells in the intestinal crypt using a new mouse model. “In most studies two mouse strains are compared (for example, wild-type versus gene-deficient) but these mice might differ in their microbiota or inflammatory tonus, affecting data interpretation,” explains Andreas Diefenbach, senior author of the study. “We generated mice with mosaic expression of the IL-22 receptor within the intestinal epithelium, resulting in mice in which some crypts lost IL-22 receptor expression next to crypts that retained it. This approach enabled analysis of IL-22 effects on the epithelium within one mouse, mitigating any confounding effects.”
When mice were treated with a carcinogen followed by dextran sodium sulfate to induce tumorigenesis, those without the IL-22 receptor in some crypts had an increased fraction of tumours, suggesting that absence of IL-22 signalling predisposes epithelial cells to carcinogenesis. Transcriptional profiling showed that ISCs lacking IL-22 signalling had reduced expression of genes involved in DNA repair, DDR and apoptosis. Investigation of the steps of DDR in ISCs following exposure to genotoxic stress demonstrated that IL-22 has a role in DDR initiation via induction of ATM expression through STAT3 signalling. Further work suggested that increased tumorigenesis in the absence of IL-22 is caused by a decreased rate of apoptosis and by accumulation of mutations.
In the colon, CD4+ T cells and group 3 innate lymphoid cells (ILC3s) are the main producers of IL-22, followed by FOXP3+CD4+ T cells and γδ T cells. Glucosinolates are phytochemicals found in cruciferous vegetables, of which some are potent genotoxins. The researchers found that treatment of mice with a glucosinolate metabolite increased IL-22 production by ILC3s and γδ T cells, which was dependent on aryl hydrocarbon receptor signalling. When mice with intact IL-22 signalling were fed a diet without glucosinolates, their colonic ILC3s and γδ T cells did not produce IL-22 and epithelial cells had an impaired DDR following DNA damage.
“Our study adds to findings that the roles of the immune system go beyond defense against pathogens. The data reveal a homeostatic network by which the immune system senses genotoxic compounds contained in nutrients and generates an output (IL-22) that adapts stem cell function to cope with genotoxic stress,” summarizes Diefenbach. “The findings might stimulate further research into how dietary compounds might influence the intestinal immune status.”
Gronke, K. et al. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature 566, 249–253 (2019)
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Thoma, C. IL-22 assures gut homeostasis. Nat Rev Gastroenterol Hepatol 16, 199 (2019). https://doi.org/10.1038/s41575-019-0124-z