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Nat Commun. 2018 Sep 18;9(1):3797. doi: 10.1038/s41467-018-06085-5.

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

Author information

1
Kennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY, United Kingdom.
2
Genentech, Department of Cancer Immunology, South San Francisco, CA, 94080, USA.
3
Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom.
4
Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
5
Department of Gastroenterology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
6
Ludwig Institute of Cancer Research, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
7
Kennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY, United Kingdom. fiona.powrie@kennedy.ox.ac.uk.

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.

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