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 2

Epithelial IL-23 signaling initiates calcium flux and promotes glycolysis.

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Epithelial IL-23 signaling initiates calcium flux and promotes glycolysi...
(A) Western blots (left) and quantification (right) of IL-23R expression in total kidneys from B6 mice administered the indicated MC for 24 hours. (B) Cryosections of kidneys from mice subjected to IL-23 MC administration for the indicated time. Magnification, ×5; scale bar: 120 μm. (C) Heatmap of PCR array showing differential expression of 22 genes in primary TECs sorted from naive mice or mice subjected to the indicated MC for 72 hours. Primary proximal TECs were isolated from B6 mice and selectively enriched in vitro (D–H). (D) Heatmap of PCR array showing differential expression of 22 genes in cultured TECs stimulated with IL-23 for the indicated hours. (E) Cumulative results of the mean fluorescence ratio of indo-1 violet versus indo-1 blue, which represent intracellular calcium flux. TECs were prestimulated with IL-23 for 6 hours and then restimulated with IL-23 (negative control: PBS; positive control: ionomycin). (F) Left: Representative mean ECAR of cultured TECs prestimulated with IL-23 for 6 hours with or without addition of EGTA and unstimulated cells as control. Dot plots represent cumulative data of calculated glycolysis (middle) and glycolytic capacity (right). (G) Western blots (left) and quantification (right) of the expression of the indicated proteins in TECs stimulated with IL-23 or PBS for 48 hours. (H) Immunofluorescence image analysis of IL-23R (green) and CaMK4 (red) expression in TECs stimulated with IL-23 for the indicated hours (DAPI as nuclear counterstain, blue). Magnification, ×63; scale bar: 10 μm. (I) Representative images of immunohistochemical (IHC) staining of CaMK4 (upper) or CaMK2 (lower) in kidneys from mice subjected to the indicated MC for 2 months; boxed areas were digitally magnified. Magnification, ×20; scale bar: 25 μm. *P < 0.05, ***P < 0.005 vs. control by Student’s t test. n = 4–6 per group in each experiment for 2 independent experiments.