Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration.

Abstract

Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch and epidermal growth factor (EGF) signals supporting Lgr5(+) crypt base columnar ISCs for normal epithelial maintenance. However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury, increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal epithelium, activating ISCs to promote regeneration.

• Authors: Caroline A Lindemans, Marco Calafiore, Anna M Mertelsmann, Margaret H O'Connor, Jarrod A Dudakov, Robert R Jenq, Enrico Velardi, Lauren F Young, Odette M Smith, Gillian Lawrence, Juliet A Ivanov, Ya-Yuan Fu, Shuichiro Takashima, Guoqiang Hua, Maria L Martin, Kevin P O'Rourke, Yuan-Hung Lo, Michal Mokry, Monica Romera-Hernandez, Tom Cupedo, Lukas Dow, Edward E Nieuwenhuis, Noah F Shroyer, Chen Liu, Richard Kolesnick, Marcel R M van den Brink, Alan M Hanash
• Journal: Nature (Nature) Vol. 528 Issue 7583 Pg. 560-564 (Dec 24 2015) ISSN: 1476-4687 [Electronic] England
• PMID: 26649819 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukins
• STAT3 Transcription Factor
• STAT3 protein, human
• Stat3 protein, mouse

Topics

• Animals
• Epithelial Cells (cytology, immunology, pathology)
• Female
• Graft vs Host Disease (pathology)
• Humans
• Immunity, Mucosal
• Interleukins (deficiency, immunology)
• Intestinal Mucosa (cytology, immunology, pathology)
• Intestine, Small (cytology, immunology, pathology)
• Mice
• Organoids (cytology, growth & development, immunology)
• Paneth Cells (cytology)
• Phosphorylation
• Regeneration
• STAT3 Transcription Factor (metabolism)
• Signal Transduction
• Stem Cell Niche
• Stem Cells (cytology, metabolism)
• Interleukin-22