Abstract
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;Sprouty2F/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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Count
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects
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Child
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Colitis / chemically induced
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Colitis / genetics*
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Colitis / metabolism
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Colitis / pathology
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Colon / drug effects
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Colon / metabolism
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Colon / pathology
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Female
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Gene Expression Regulation
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Glycogen Synthase Kinase 3 beta / genetics*
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Glycogen Synthase Kinase 3 beta / metabolism
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Goblet Cells / drug effects
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Goblet Cells / metabolism
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Goblet Cells / pathology
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HT29 Cells
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Homeostasis / drug effects
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Homeostasis / genetics*
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Humans
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Interleukin-33 / genetics*
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Interleukin-33 / metabolism
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / pathology
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Male
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction
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Sodium Dodecyl Sulfate / administration & dosage
Substances
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Il33 protein, mouse
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Interleukin-33
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Membrane Proteins
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Microfilament Proteins
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Vil1 protein, mouse
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Sodium Dodecyl Sulfate
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Spry2 protein, mouse