IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation
Hao Li, … , Jarrat Jordan, George C. Tsokos
Hao Li, … , Jarrat Jordan, George C. Tsokos
Published May 6, 2021
Citation Information: J Clin Invest. 2021;131(12):e142428. https://doi.org/10.1172/JCI142428.
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Research Article Autoimmunity

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

Abstract

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.

Authors

Hao Li, Maria G. Tsokos, Rhea Bhargava, Iannis E. Adamopoulos, Hanni Menn-Josephy, Isaac E. Stillman, Philip Rosenstiel, Jarrat Jordan, George C. Tsokos

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Figure 4

Genetic deficiency of Il23r or Camk4 ameliorates, but deficiency of Arg1 exaggerates, renal inflammation in mice.

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Genetic deficiency of Il23r or Camk4 ameliorates, but deficiency of Arg1...
All mice were Cdh16-cre+: Cdh16-Cre (control), Cdh16-Cre × Il23rfl/fl (Il23rΔTEC), Cdh16-Cre × Camk4fl/fl (Camk4ΔTEC), and Cdh16-Cre × Arg1fl/fl (Arg1ΔTEC). Eight-week-old mice with the indicated genotype were injected with IL-23 MC for 90 days (A–C). (A) Representative images of H&E-stained kidney sections from the indicated mice; boxed areas were digitally magnified. Magnification, ×5; scale bar: 200 μm. (B) Flow cytometric quantification of infiltrating CD4+ T cells and activated macrophages/neutrophils in kidneys. (C) Histopathologic scoring of kidneys from the indicated mice. (D) ELISA quantification of protein in urine from the indicated mice. Left: Urine β-2-microglobulin from the indicated mice. Right: The mean ratio of urine albumin and creatinine from the indicated mice. **P < 0.01, ***P < 0.005 versus control by 2-way ANOVA. Sheep anti–mouse glomerular basement membrane (anti-GBM) serum (100 μL in E–G or 50 μL in H–J) was administered to 8-week-old mice with the indicated genotype for 21 days for the induction of immune-mediated glomerulonephritis. (E) Representative images of H&E, PAS, and Masson’s trichrome staining of kidneys from the indicated 3 groups of mice subjected to sheep anti–mouse GBM serum. Magnification, ×20; scale bar: 40 μm. (F) Flow cytometric quantification of infiltrating CD4+ T cells and activated macrophages/neutrophils in kidneys. (G) Histopathologic scoring of kidneys from the indicated mice. (H) Representative images of H&E, PAS, and Masson’s trichrome staining of kidneys from the indicated 2 groups of mice subjected to sheep anti–mouse GBM serum. Magnification, ×20; scale bar: 40 μm. (I) Flow cytometric quantification of infiltrating CD4+ T cells and activated macrophages/neutrophils in kidneys. (J) Histopathologic scoring of kidneys from the indicated mice. Data represent the mean ± SEM; n = 5–7 mice per group in each experiment for 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.005 versus control by Student’s t test.