Pro-inflammatory secretome from intestinal epithelium recruits regulatory T cells for barrier defence

Resolution of inflammation, including of colitis, requires carefully coordinated communication between different tissues. While the role of immune cells in colitis is well established, less is known about epithelial communication to its microenvironment. Most secreted factors that comprise cellular communication are directly regulated by the transcription factor NF-κB. However, which transcriptomes NF-κB regulates in epithelium during colitis progression and whether these transcriptomes exacerbate or protect from colitis remains controversial. Here we use colonic biopsies from patients with ulcerative colitis (UC) and novel mouse models that permit specific visualisation of NF-κB in all tissues. Single-cell RNA sequencing and secretome analysis were combined to define epithelial communication at different stages of murine colitis and UC. We demonstrated that paradoxically, the NF-κB-directed pro-inflammatory secretome from the intestinal epithelial cells (IEC) is essential for recovery and for deterrence of unrestrained inflammation. Mechanistically, IEC NF-κB recruits and reprograms tolerogenic regulatory T cells that mediate protection from colitis. In ulcerative colitis patients, IEC NF-κB is not uniformly activated, as previously believed, but rather switches on transcription of select pro-inflammatory genes with concomitant repression of targets regulating T cell recruitment. Our findings map the dynamic changes of epithelial communication to mucosal leukocytes and identify a crucial protective mechanism initiated by IEC essential for resolution and recovery.