IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31722-5.html
   My bibliography  Save this article

Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity

Author

Listed:
  • Joachim Hanna

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Flavio Beke

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Louise M. O’Brien

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Chrysa Kapeni

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Hung-Chang Chen

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Valentina Carbonaro

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Alexander B. Kim

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Kamal Kishore

    (Cancer Research UK Cambridge Institute, University of Cambridge)

  • Timon E. Adolph

    (Medical University Innsbruck)

  • Mikkel-Ole Skjoedt

    (Rigshospitalet - University Hospital Copenhagen
    University of Copenhagen)

  • Karsten Skjoedt

    (University of Southern Denmark)

  • Marc Roche

    (Department of Biochemistry, University of Cambridge)

  • Maike Roche

    (Cancer Research UK Cambridge Institute, University of Cambridge)

Abstract

Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell fate decisions during embryogenesis and adult tissue patterning. Here we find that cell-autonomous Hedgehog signaling, independent of exogenous ligands, selectively drives the polarization of Th17 cells but not other T helper cell subsets. We show that endogenous Hedgehog ligand, Ihh, signals to activate both canonical and non-canonical Hedgehog pathways through Gli3 and AMPK. We demonstrate that Hedgehog pathway inhibition with either the clinically-approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4+ T cells greatly diminishes disease severity in two mouse models of intestinal inflammation. We confirm that Hedgehog pathway expression is upregulated in tissue from human ulcerative colitis patients and correlates with Th17 marker expression. This work implicates Hedgehog signaling in Th17 polarization and intestinal immunopathology and indicates the potential therapeutic use of Hedgehog inhibitors in the treatment of inflammatory bowel disease.

Suggested Citation

  • Joachim Hanna & Flavio Beke & Louise M. O’Brien & Chrysa Kapeni & Hung-Chang Chen & Valentina Carbonaro & Alexander B. Kim & Kamal Kishore & Timon E. Adolph & Mikkel-Ole Skjoedt & Karsten Skjoedt & Ma, 2022. "Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31722-5
    DOI: 10.1038/s41467-022-31722-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31722-5
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-31722-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Yael Haberman & Rebekah Karns & Phillip J. Dexheimer & Melanie Schirmer & Judith Somekh & Ingrid Jurickova & Tzipi Braun & Elizabeth Novak & Laura Bauman & Margaret H. Collins & Angela Mo & Michael J., 2019. "Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    2. Jane C. Stinchcombe & Endre Majorovits & Giovanna Bossi & Stephen Fuller & Gillian M. Griffiths, 2006. "Centrosome polarization delivers secretory granules to the immunological synapse," Nature, Nature, vol. 443(7110), pages 462-465, September.
    3. Timon E. Adolph & Michal F. Tomczak & Lukas Niederreiter & Hyun-Jeong Ko & Janne Böck & Eduardo Martinez-Naves & Jonathan N. Glickman & Markus Tschurtschenthaler & John Hartwig & Shuhei Hosomi & Magda, 2013. "Paneth cells as a site of origin for intestinal inflammation," Nature, Nature, vol. 503(7475), pages 272-276, November.
    4. Enric Esplugues & Samuel Huber & Nicola Gagliani & Anja E. Hauser & Terrence Town & Yisong Y. Wan & William O’Connor & Anthony Rongvaux & Nico Van Rooijen & Ann M. Haberman & Yoichiro Iwakura & Vijay , 2011. "Control of TH17 cells occurs in the small intestine," Nature, Nature, vol. 475(7357), pages 514-518, July.
    5. Jane C. Stinchcombe & Endre Majorovits & Giovanna Bossi & Stephen Fuller & Gillian M. Griffiths, 2006. "Erratum: Centrosome polarization delivers secretory granules to the immunological synapse," Nature, Nature, vol. 444(7116), pages 236-236, November.
    6. Jussi Taipale & Philip A. Beachy, 2001. "The Hedgehog and Wnt signalling pathways in cancer," Nature, Nature, vol. 411(6835), pages 349-354, May.
    7. Jun R. Huh & Monica W. L. Leung & Pengxiang Huang & Daniel A. Ryan & Michael R. Krout & Raghu R. V. Malapaka & Jonathan Chow & Nicolas Manel & Maria Ciofani & Sangwon V. Kim & Adolfo Cuesta & Fabio R., 2011. "Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORγt activity," Nature, Nature, vol. 472(7344), pages 486-490, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Mitchell S. Wang & Yuesong Hu & Elisa E. Sanchez & Xihe Xie & Nathan H. Roy & Miguel Jesus & Benjamin Y. Winer & Elizabeth A. Zale & Weiyang Jin & Chirag Sachar & Joanne H. Lee & Yeonsun Hong & Minsoo, 2022. "Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Xingxing Ren & Qiuyuan Liu & Peirong Zhou & Tingyue Zhou & Decai Wang & Qiao Mei & Richard A. Flavell & Zhanju Liu & Mingsong Li & Wen Pan & Shu Zhu, 2024. "DHX9 maintains epithelial homeostasis by restraining R-loop-mediated genomic instability in intestinal stem cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Gaetane Nocturne & Stephan Pavy & Saida Boudaoud & Raphaèle Seror & Philippe Goupille & Philippe Chanson & Désirée van der Heijde & Floris van Gaalen & Francis Berenbaum & Xavier Mariette & Karine Bri, 2015. "Increase in Dickkopf-1 Serum Level in Recent Spondyloarthritis. Data from the DESIR Cohort," PLOS ONE, Public Library of Science, vol. 10(8), pages 1-16, August.
    4. Ran Song & William McAlpine & Aaron M. Fond & Evan Nair-Gill & Jin Huk Choi & Elisabeth E. L. Nyström & Liisa Arike & Sydney Field & Xiaohong Li & Jeffrey A. SoRelle & James J. Moresco & Eva Marie Y. , 2023. "Trans-Golgi protein TVP23B regulates host-microbe interactions via Paneth cell homeostasis and Goblet cell glycosylation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Cummings, F.W, 2004. "A model of morphogenesis," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 339(3), pages 531-547.
    6. Tzipi Braun & Rui Feng & Amnon Amir & Nina Levhar & Hila Shacham & Ren Mao & Rotem Hadar & Itamar Toren & Yadid Algavi & Kathleen Abu-Saad & Shuoyu Zhuo & Gilat Efroni & Alona Malik & Orit Picard & Mi, 2024. "Diet-omics in the Study of Urban and Rural Crohn disease Evolution (SOURCE) cohort," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    7. Jorge Mata-Garrido & Yao Xiang & Yunhua Chang-Marchand & Caroline Reisacher & Elisabeth Ageron & Ida Chiara Guerrera & Iñigo Casafont & Aurelia Bruneau & Claire Cherbuy & Xavier Treton & Anne Dumay & , 2022. "The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Indra Adrianto & Chee Paul Lin & Jessica J Hale & Albert M Levin & Indrani Datta & Ryan Parker & Adam Adler & Jennifer A Kelly & Kenneth M Kaufman & Christopher J Lessard & Kathy L Moser & Robert P Ki, 2012. "Genome-Wide Association Study of African and European Americans Implicates Multiple Shared and Ethnic Specific Loci in Sarcoidosis Susceptibility," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-10, August.
    9. Stéphanie Bibert & Mathieu Quinodoz & Sylvain Perriot & Fanny S. Krebs & Maxime Jan & Rita C. Malta & Emilie Collinet & Mathieu Canales & Amandine Mathias & Nicole Faignart & Eliane Roulet-Perez & Pas, 2024. "Herpes simplex encephalitis due to a mutation in an E3 ubiquitin ligase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    10. Wen-Lan Yang & Weinan Qiu & Ting Zhang & Kai Xu & Zi-Juan Gu & Yu Zhou & Heng-Ji Xu & Zhong-Zhou Yang & Bin Shen & Yong-Liang Zhao & Qi Zhou & Ying Yang & Wei Li & Peng-Yuan Yang & Yun-Gui Yang, 2023. "Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Felicite K. Noubissi & Clement G. Yedjou & Vladimir S. Spiegelman & Paul B. Tchounwou, 2018. "Cross-Talk between Wnt and Hh Signaling Pathways in the Pathology of Basal Cell Carcinoma," IJERPH, MDPI, vol. 15(7), pages 1-13, July.
    12. Johanne Brooks-Warburton & Dezso Modos & Padhmanand Sudhakar & Matthew Madgwick & John P. Thomas & Balazs Bohar & David Fazekas & Azedine Zoufir & Orsolya Kapuy & Mate Szalay-Beko & Bram Verstockt & L, 2022. "A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31722-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.