IL-17A Produced by Innate Lymphoid Cells Is Essential for Intestinal Ischemia-Reperfusion Injury

J Immunol. 2017 Oct 15;199(8):2921-2929. doi: 10.4049/jimmunol.1700655. Epub 2017 Sep 6.

Abstract

Ischemia-reperfusion (IR) injury to the small intestine following clamping of the superior mesenteric artery results in an intense local inflammatory response that is characterized by villous damage and neutrophil infiltration. IL-17A, a cytokine produced by a variety of cells in response to inflammatory cytokines released following tissue injury, has been implicated in IR injury. Using Il17a-/- , Il23r-/- , and Rorc-/- mice and administration of anti-IL-17A and anti-IL-23 neutralizing Abs to wild-type mice, we demonstrate that intestinal IR injury depends on IL-17A and that IL-17A is downstream of the binding of autoantibody to ischemia-conditioned tissues and subsequent complement activation. Using bone marrow chimeras, we demonstrate that the IL-17A required for intestinal IR injury is derived from hematopoietic cells. Finally, by transferring autoantibody-rich sera into Rag2γc-/- and Rag2-/- mice, we demonstrate that innate lymphoid cells are the main producers of IL-17A in intestinal IR injury. We propose that local production of IL-17A by innate lymphoid cells is crucial for the development of intestinal IR injury and may provide a therapeutic target for clinical exploitation.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Blocking / administration & dosage
  • Autoantibodies / metabolism
  • Cells, Cultured
  • Complement Activation
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Humans
  • Immunity, Innate
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Intestine, Small / immunology*
  • Intestine, Small / pathology*
  • Lymphocytes / immunology*
  • Mesenteric Artery, Superior / surgery
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Receptors, Interleukin / genetics
  • Reperfusion Injury / immunology*

Substances

  • Antibodies, Blocking
  • Autoantibodies
  • DNA-Binding Proteins
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Rag2 protein, mouse
  • Receptors, Interleukin
  • Rorc protein, mouse
  • interleukin-23 receptor, mouse