Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33.

Autor: Schumacher MA; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.; Department of Pediatrics and Department of Biochemistry and Molecular Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA., Hsieh JJ; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.; Department of Pediatrics and Department of Biochemistry and Molecular Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA., Liu CY; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA., Appel KL; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA., Waddell A; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA., Almohazey D; Department of Stem Cell Research, Institute for Research and Medical Consultation (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia., Katada K; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA., Bernard JK; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA., Bucar EB; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.; Department of Pediatrics and Department of Biochemistry and Molecular Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA., Gadeock S; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA., Maselli KM; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA., Washington MK; Departments of Pathology, Microbiology, and Immunology, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA., Grikscheit TC; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Warburton D; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA., Rosen MJ; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA., Frey MR; The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA. mfrey@chla.usc.edu.; Department of Pediatrics and Department of Biochemistry and Molecular Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. mfrey@chla.usc.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Feb 05; Vol. 12 (1), pp. 836. Date of Electronic Publication: 2021 Feb 05.
DOI: 10.1038/s41467-021-21113-7
Abstrakt: Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we ask whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion leads to expanded tuft and goblet cell populations. Sprouty2 loss induces PI3K/Akt signaling, leading to GSK3β inhibition and epithelial interleukin (IL)-33 expression. In vivo, this results in increased stromal IL-13+ cells. IL-13 in turn induces tuft and goblet cell expansion in vitro and in vivo. Sprouty2 is downregulated by acute inflammation; this appears to be a protective response, as VillinCre;Sprouty2 F/F mice are resistant to DSS colitis. In contrast, Sprouty2 is elevated in chronic colitis and in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.
Databáze: MEDLINE
Externí odkaz: