IL-22 promotes mucin-type O-glycosylation and MATH1+ cell-mediated amelioration of intestinal inflammation

  • Cell Rep. 2024 May 28;43(5):114206. doi: 10.1016/j.celrep.2024.114206.
Ankita Singh  1 ,  Michael Beaupre  1 ,  Cecilia Villegas-Novoa  2 ,  Kiyoshi Shiomitsu  1 ,  Stephen J Gaudino  1 ,  Suzanne Tawch  1 ,  Ruhee Damle  1 ,  Cody Kempen  1 ,  Biswa Choudhury  3 ,  Jeremy P McAleer  4 ,  Brian S Sheridan  1 ,  Paula Denoya  5 ,  Richard S Blumberg  6 ,  Patrick Hearing  1 ,  Nancy L Allbritton  2 ,  Pawan Kumar  7
Affiliations
  • 1. Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
  • 2. Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
  • 3. GlycoAnalytics Core, University of California, San Diego, La Jolla, CA 92093, USA.
  • 4. Department of Pharmaceutical Sciences, Marshall University School of Pharmacy, Huntington, WV 25701, USA.
  • 5. Division of Colon and Rectal Surgery, Department of Surgery, Stony Brook University Hospital, Stony Brook, NY 11794, USA.
  • 6. Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 7. Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: [email protected].
PMID: 38733584 DOI: 10.1016/j.celrep.2024.114206
Abstract

The interleukin (IL)-22 cytokine can be protective or inflammatory in the intestine. It is unclear if IL-22 Receptor (IL-22Ra1)-mediated protection involves a specific type of intestinal epithelial cell (IEC). By using a range of IEC type-specific Il22Ra1 conditional knockout mice and a dextran sulfate sodium (DSS) colitis model, we demonstrate that IL-22Ra1 signaling in MATH1+ cells (goblet and progenitor cells) is essential for maintaining the mucosal barrier and intestinal tissue regeneration. The IL-22Ra1 signaling in IECs promotes Mucin core-2 O-glycan extension and induces beta-1,3-galactosyltransferase 5 (B3GALT5) expression in the colon. Adenovirus-mediated expression of B3galt5 is sufficient to rescue Il22Ra1IEC mice from DSS colitis. Additionally, we observe a reduction in the expression of B3GALT5 and the Tn antigen, which indicates defective Mucin O-glycan, in the colon tissue of patients with ulcerative colitis. Lastly, IL-22Ra1 signaling in MATH1+ progenitor cells promotes Organoid regeneration after DSS injury. Our findings suggest that IL-22-dependent protective responses involve O-glycan modification, proliferation, and differentiation in MATH1+ progenitor cells.

Keywords
B3GALT5; CP: Immunology; IL-22; IL-22Ra1; MATH1; O-glycan; STAT3; colitis; epithelium; mucin; regeneration.
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