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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells
  • Bone Marrow Transplantation
  • Colitis / immunology*
  • Colitis / microbiology
  • Colitis / pathology
  • Colon
  • Disease Models, Animal
  • Female
  • Helicobacter Infections / immunology*
  • Helicobacter Infections / microbiology
  • Helicobacter Infections / pathology
  • Helicobacter hepaticus / immunology
  • Humans
  • Inflammatory Bowel Diseases / immunology*
  • Inflammatory Bowel Diseases / microbiology
  • Inflammatory Bowel Diseases / pathology
  • Interleukin-12 / immunology*
  • Interleukin-12 / metabolism
  • Interleukin-23 / immunology
  • Interleukin-23 / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Primary Cell Culture
  • Protein Kinases / genetics
  • Protein Kinases / immunology
  • Protein Kinases / metabolism*
  • Radiation Chimera
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism

Substances

  • Interleukin-23
  • Interleukin-12
  • ALPK1 protein, mouse
  • Protein Kinases