Paneth cell-mediated multiorgan dysfunction after acute kidney injury

J Immunol. 2012 Dec 1;189(11):5421-33. doi: 10.4049/jimmunol.1200581. Epub 2012 Oct 29.


Acute kidney injury (AKI) is frequently complicated by extrarenal multiorgan injury, including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of proinflammatory mediators drives multiorgan injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage-depleted mice decreased markedly. In addition, intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Kidney Injury / complications
  • Acute Kidney Injury / immunology
  • Acute Kidney Injury / pathology*
  • Animals
  • Apoptosis
  • Inflammation / complications
  • Inflammation / immunology
  • Inflammation / pathology*
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / immunology
  • Kidney / immunology
  • Kidney / pathology*
  • Lung / immunology
  • Lung / pathology*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Nephrectomy
  • Paneth Cells / immunology
  • Paneth Cells / pathology*
  • Portal System / immunology
  • Reperfusion Injury / complications
  • Reperfusion Injury / immunology
  • Reperfusion Injury / pathology*


  • Interleukin-17