Wnt/β-catenin Maintains Epithelial IL-33 in the Colonic Stem and Progenitor Cell Niche and Drives Its Induction in Colitis

Overview

Journal Mucosal Immunol

Publisher Elsevier

Specialty Allergy & Immunology

Date 2024 Nov 26

PMID 39592069

Authors

Michael A Schumacher

Megan H Thai

Jonathan J Hsieh

Alexa Gramajo

Cambrian Y Liu

Mark R Frey

Affiliations

Soon will be listed here.

Abstract

Interleukin (IL)-33 is a key responder to intestinal injury and inflammation. In the colon, it is expressed by several cell populations, with the specific cellular source likely determining its role. The colonic epithelium expresses IL-33; however, the factors controlling its production and the specific epithelial lineage(s) expressing IL-33 are poorly understood. We recently reported that colonic epithelial IL-33 is induced by inhibition of glycogen synthase kinase-3β (GSK3β), but the signaling pathway mediating this induction is unknown. Here we tested the role of Wnt/β-catenin signaling in regulating colonic epithelial IL-33 at homeostasis and in injury-induced colitis. Transcriptomic analysis shows that epithelial IL-33 localizes to stem and progenitor cells. Ligand activation of Wnt/β-catenin signaling induced IL-33 in colonic organoid and cell cultures. Furthermore, small-molecule disruption of β-catenin interaction with cyclic AMP response element binding protein (CBP) prevented epithelial IL-33 induction. Antagonism of CBP/β-catenin signaling also prevented rapid epithelial IL-33 induction in dextran sodium sulfate (DSS)-mediated colitis, and was associated with maintenance of crypt-expressed host defense peptides. Together, these findings show β-catenin-driven production of epithelial IL-33 is an early response to colonic injury that shapes the crypt base defense response and suggest an immunoregulatory role for the stem cell niche in tissue injury.

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References

Bergstrom K, Morampudi V, Chan J, Bhinder G, Lau J, Yang H . Goblet Cell Derived RELM-β Recruits CD4+ T Cells during Infectious Colitis to Promote Protective Intestinal Epithelial Cell Proliferation. PLoS Pathog. 2015; 11(8):e1005108. PMC: 4540480. DOI: 10.1371/journal.ppat.1005108. View

Deng F, Peng L, Li Z, Tan G, Liang E, Chen S . YAP triggers the Wnt/β-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury. Cell Death Dis. 2018; 9(2):153. PMC: 5833613. DOI: 10.1038/s41419-017-0244-8. View

Farin H, Karthaus W, Kujala P, Rakhshandehroo M, Schwank G, Vries R . Paneth cell extrusion and release of antimicrobial products is directly controlled by immune cell-derived IFN-γ. J Exp Med. 2014; 211(7):1393-405. PMC: 4076587. DOI: 10.1084/jem.20130753. View

Hung L, Tanaka Y, Herbine K, Pastore C, Singh B, Ferguson A . Cellular context of IL-33 expression dictates impact on anti-helminth immunity. Sci Immunol. 2020; 5(53). PMC: 8257082. DOI: 10.1126/sciimmunol.abc6259. View

Howitt M, Lavoie S, Michaud M, Blum A, Tran S, Weinstock J . Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science. 2016; 351(6279):1329-33. PMC: 5528851. DOI: 10.1126/science.aaf1648. View

Bansal K, Trinath J, Chakravortty D, Patil S, Balaji K . Pathogen-specific TLR2 protein activation programs macrophages to induce Wnt-beta-catenin signaling. J Biol Chem. 2011; 286(42):37032-44. PMC: 3196083. DOI: 10.1074/jbc.M111.260414. View

Lopetuso L, De Salvo C, Pastorelli L, Rana N, Senkfor H, Petito V . IL-33 promotes recovery from acute colitis by inducing miR-320 to stimulate epithelial restitution and repair. Proc Natl Acad Sci U S A. 2018; 115(40):E9362-E9370. PMC: 6176569. DOI: 10.1073/pnas.1803613115. View

Nava P, Koch S, Laukoetter M, Lee W, Kolegraff K, Capaldo C . Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity. 2010; 32(3):392-402. PMC: 2859189. DOI: 10.1016/j.immuni.2010.03.001. View

Blyth G, Connors L, Fodor C, Cobo E . The Network of Colonic Host Defense Peptides as an Innate Immune Defense Against Enteropathogenic Bacteria. Front Immunol. 2020; 11:965. PMC: 7251035. DOI: 10.3389/fimmu.2020.00965. View

10.

Zhu P, Zhu X, Wu J, He L, Lu T, Wang Y . IL-13 secreted by ILC2s promotes the self-renewal of intestinal stem cells through circular RNA circPan3. Nat Immunol. 2019; 20(2):183-194. DOI: 10.1038/s41590-018-0297-6. View

11.

Schiering C, Krausgruber T, Chomka A, Frohlich A, Adelmann K, Wohlfert E . The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature. 2014; 513(7519):564-568. PMC: 4339042. DOI: 10.1038/nature13577. View

12.

Maywald R, Doerner S, Pastorelli L, De Salvo C, Benton S, Dawson E . IL-33 activates tumor stroma to promote intestinal polyposis. Proc Natl Acad Sci U S A. 2015; 112(19):E2487-96. PMC: 4434739. DOI: 10.1073/pnas.1422445112. View

13.

Neill D, Wong S, Bellosi A, Flynn R, Daly M, Langford T . Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010; 464(7293):1367-70. PMC: 2862165. DOI: 10.1038/nature08900. View

14.

Clevers H . Wnt/beta-catenin signaling in development and disease. Cell. 2006; 127(3):469-80. DOI: 10.1016/j.cell.2006.10.018. View

15.

Martin N, Martin M . Interleukin 33 is a guardian of barriers and a local alarmin. Nat Immunol. 2016; 17(2):122-31. DOI: 10.1038/ni.3370. View

16.

Sedhom M, Pichery M, Murdoch J, Foligne B, Ortega N, Normand S . Neutralisation of the interleukin-33/ST2 pathway ameliorates experimental colitis through enhancement of mucosal healing in mice. Gut. 2012; 62(12):1714-23. PMC: 3841767. DOI: 10.1136/gutjnl-2011-301785. View

17.

Amit S, Hatzubai A, Birman Y, Andersen J, Ben-Shushan E, Mann M . Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 2002; 16(9):1066-76. PMC: 186245. DOI: 10.1101/gad.230302. View

18.

Borrelli C, Valenta T, Handler K, Velez K, Gurtner A, Moro G . Differential regulation of β-catenin-mediated transcription via N- and C-terminal co-factors governs identity of murine intestinal epithelial stem cells. Nat Commun. 2021; 12(1):1368. PMC: 7921392. DOI: 10.1038/s41467-021-21591-9. View

19.

Fong C, Leong H, Wong E, Lim J, Yusoff P, Guy G . Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function. J Biol Chem. 2003; 278(35):33456-64. DOI: 10.1074/jbc.M301317200. View

20.

Sun Y, Kolligs F, Hottiger M, Mosavin R, Fearon E, Nabel G . Regulation of beta -catenin transformation by the p300 transcriptional coactivator. Proc Natl Acad Sci U S A. 2000; 97(23):12613-8. PMC: 18812. DOI: 10.1073/pnas.220158597. View