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 6

Upregulation of IL-23R and CaMK4 aligned with the reduction of ARG1 in renal biopsies from patients with glomerulonephritis.

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Upregulation of IL-23R and CaMK4 aligned with the reduction of ARG1 in r...
Human proximal TECs were cultured in vitro and stimulated with or without IL-23. (A) Left: Representative mean ECAR of TECs prestimulated with IL-23 for 6 hours (PBS as control, blue) with (green) or without (red) addition of EGTA. Dot plots represent cumulative data of calculated glycolysis (middle) and glycolytic capacity (right). (B) Heatmap of customized PCR array showing differential expression of 22 genes in TECs stimulated with IL-23 for the indicated hours. (C) Western blots (left) and quantification (right) of the expression of the indicated proteins in TECs stimulated with PBS or IL-23 for 48 hours. (E) Flow cytometric analysis of in vitro proliferative response (CFSElo) of purified CD4+ T cells from healthy PBMCs cocultured with TECs or IL-23–prestimulated TECs in arginine-deficient media with or without addition of arginine or citrulline for 72 hours (n = 4). T cells were stimulated with anti-CD3 and anti-CD28. (F–H) Cryosection of human kidney biopsies from the indicated group (control: healthy donor, n = 5; AR: allograft rejection, n = 7; ANCA: anti-neutrophil cytoplasmic autoantibody–associated glomerulonephritis, n = 4; LN: active lupus nephritis, n = 13). (I–K) Cryosection of human kidney biopsies from patients with indicted types of lupus nephritis (healthy donor, n = 5; class III lupus nephritis, n = 5; class IV lupus nephritis, n = 8; lupus nephritis with remission status, n = 4). (F and I) Renal biopsies stained for synaptopodin (blue), IL-23R (green), and CaMK4 (red). Magnification, ×4; scale bar: 180 μm. Top: Synaptopodin and IL-23R. Bottom: Synaptopodin and CaMK4. (G and J). Renal interstitium stained for CD26 (blue), ARG1 (red), and IL-23R (upper, green) or CaMK4 (bottom, green). (H) ImageJ intensity quantification plots. Magnification, ×20; scale bar: 50 μm. Data represent the mean ± SEM. *P < 0.05, ***P < 0.005 versus control by Student’s t test (A and D) or 2-way ANOVA (H and K).