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

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. Goettel, Joerg Ermann, Bruce H. Horwitz, Ludovico Buti, Xin Lu, Subhankar Mukhopadhyay, Scott B. Snapper and Fiona Powrie ()
Additional contact information
Grigory Ryzhakov: University of Oxford
Nathaniel R. West: University of Oxford
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

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06085-5

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