IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation

J Clin Invest. 2021 Jun 15;131(12):e142428. doi: 10.1172/JCI142428.


Interstitial kidney inflammation is present in various nephritides in which serum interleukin 23 (IL-23) is elevated. Here we showed that murine and human renal tubular epithelial cells (TECs) expressing the IL-23 receptor (IL-23R) responded to IL-23 by inducing intracellular calcium flux, enhancing glycolysis, and upregulating calcium/calmodulin kinase IV (CaMK4), which resulted in suppression of the expression of the arginine-degrading enzyme arginase 1 (ARG1), thus increasing in situ levels of free L-arginine. Limited availability of arginine suppressed the ability of infiltrating T cells to proliferate and produce inflammatory cytokines. TECs from humans and mice with nephritis expressed increased levels of IL-23R and CaMK4 but reduced levels of ARG1. TEC-specific deletion of Il23r or Camk4 suppressed inflammation, whereas deletion of Arg1 exacerbated inflammation in different murine disease models. Finally, TEC-specific delivery of a CaMK4 inhibitor specifically curbed renal inflammation in lupus-prone mice without affecting systemic inflammation. Our data offer the first evidence to our knowledge of the immunosuppressive capacity of TECs through a mechanism that involves competitive uptake of arginine and signify the importance of modulation of an inflammatory cytokine in the function of nonlymphoid cells, which leads to the establishment of an inflammatory microenvironment. New approaches to treat kidney inflammation should consider restoring the immunosuppressive capacity of TECs.

Keywords: Autoimmune diseases; Autoimmunity.

Publication types

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

MeSH terms

  • Animals
  • Arginase / genetics
  • Arginase / metabolism
  • Calcium Signaling*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Interleukin-23 / genetics
  • Interleukin-23 / metabolism*
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Mice
  • Mice, Knockout
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism


  • IL23R protein, human
  • Interleukin-23
  • Receptors, Interleukin
  • interleukin-23 receptor, mouse
  • CAMK4 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Camk4 protein, mouse
  • ARG1 protein, human
  • Arg1 protein, mouse
  • Arginase