Type III interferons induce pyroptosis in gut epithelial cells and impair tissue repair upon intestinal injury.

Tissue damage and repair are hallmarks of inflammation. Despite a wealth of information on the mechanisms that govern tissue damage, mechanistic insight on how inflammation affects repair is lacking. Here, we investigated how interferons influence tissue repair after damage to the intestinal mucosa. We found that type III, not type I or II, interferons delay epithelial cell regeneration by inducing the upregulation of Z-DNA-binding protein 1 (ZBP1). Z-nucleic acids formed following intestinal damage are sensed by ZBP1, leading to Caspase-8 activation, and cleavage of Gasdermin C (GSDMC). Cleaved GSDMC drives epithelial cell death by pyroptosis and delays repair of the large or small intestine after colitis or irradiation, respectively. The type III interferon/ZBP1/Caspase-8/GSDMC axis is also active in patients with inflammatory bowel disease (IBD). Our findings highlight the capacity of type III interferons to delay gut repair, which has important implications for IBD patients or individuals exposed to radiation therapies. Overall design: Age-matched (8–12-weeks old) cohorts of male and female mice were given 2.5% DSS drinking water for 7 days, followed by 3 days of recovery. On day 10, three mice per condition and genotype were sacrificed and colons were harvested. Single-cell RNA-sequencing was performed using 10x Genomics 3' v3.1 transcriptomics kit with mouse replicates (per tissue region) combined together and labeled with biotinylated antibodies, followed by oligo-conjugated streptavidin to differentiate between samples (using Biolegend TotalSeqB reagents).