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Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis

Author

Listed:
  • Grigory Ryzhakov

    (University of Oxford)

  • Nathaniel R. West

    (University of Oxford
    Genentech, Department of Cancer Immunology)

  • Fanny Franchini

    (University of Oxford)

  • Simon Clare

    (Wellcome Trust Sanger Institute, Hinxton)

  • Nicholas E. Ilott

    (University of Oxford)

  • Stephen N. Sansom

    (University of Oxford)

  • Samuel J. Bullers

    (University of Oxford)

  • Claire Pearson

    (University of Oxford)

  • Alice Costain

    (University of Oxford)

  • Alun Vaughan-Jackson

    (University of Oxford)

  • Jeremy A. Goettel

    (Boston Children’s Hospital and Harvard Medical School)

  • Joerg Ermann

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Bruce H. Horwitz

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Ludovico Buti

    (University of Oxford)

  • Xin Lu

    (University of Oxford)

  • Subhankar Mukhopadhyay

    (Wellcome Trust Sanger Institute, Hinxton)

  • Scott B. Snapper

    (Boston Children’s Hospital and Harvard Medical School)

  • Fiona Powrie

    (University of Oxford)

Abstract

Inflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs. However, the specific gene that controls disease susceptibility remains unknown. Here we identify a Hiccs locus gene, Alpk1 (encoding alpha kinase 1), as a potent regulator of intestinal inflammation. In response to infection with the commensal pathobiont Helicobacter hepaticus (Hh), Alpk1-deficient mice display exacerbated interleukin (IL)-12/IL-23 dependent colitis characterized by an enhanced Th1/interferon(IFN)-γ response. Alpk1 controls intestinal immunity via the hematopoietic system and is highly expressed by mononuclear phagocytes. In response to Hh, Alpk1−/− macrophages produce abnormally high amounts of IL-12, but not IL-23. This study demonstrates that Alpk1 promotes intestinal homoeostasis by regulating the balance of type 1/type 17 immunity following microbial challenge.

Suggested Citation

  • Grigory Ryzhakov & Nathaniel R. West & Fanny Franchini & Simon Clare & Nicholas E. Ilott & Stephen N. Sansom & Samuel J. Bullers & Claire Pearson & Alice Costain & Alun Vaughan-Jackson & Jeremy A. Goe, 2018. "Alpha kinase 1 controls intestinal inflammation by suppressing the IL-12/Th1 axis," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06085-5
    DOI: 10.1038/s41467-018-06085-5
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