Kidney VISTA prevents IFN-γ/IL-9 axis–mediated tubulointerstitial fibrosis after acute glomerular injury
Min-Gang Kim, … , Dong-Sup Lee, Seung Seok Han
Min-Gang Kim, … , Dong-Sup Lee, Seung Seok Han
Published November 9, 2021
Citation Information: J Clin Invest. 2022;132(1):e151189. https://doi.org/10.1172/JCI151189.
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Research Article Nephrology

Kidney VISTA prevents IFN-γ/IL-9 axis–mediated tubulointerstitial fibrosis after acute glomerular injury

Abstract

Severe glomerular injury ultimately leads to tubulointerstitial fibrosis that determines patient outcome, but the immunological molecules connecting these processes remain undetermined. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir–/–) kidney suffered more damage than those in WT kidneys. When interstitial immune cells were examined, the contact frequency of macrophages with infiltrated T cells increased and the immunometabolic features of T cells changed to showing high oxidative phosphorylation and fatty acid metabolism and overproduction of IFN-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more IL-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against IFN-γ and IL-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., antineutrophil cytoplasmic autoantibody vasculitis), high VISTA expression in tubulointerstitial immune cells was associated with low tubulointerstitial fibrosis and good prognosis. Therefore, VISTA is a sentinel protein expressed in kidney macrophages that prevents tubulointerstitial fibrosis via the IFN-γ/IL-9 axis after acute antibody-mediated glomerular injury.

Authors

Min-Gang Kim, Donghwan Yun, Chae Lin Kang, Minki Hong, Juhyeon Hwang, Kyung Chul Moon, Chang Wook Jeong, Cheol Kwak, Dong Ki Kim, Kook-Hwan Oh, Kwon Wook Joo, Yon Su Kim, Dong-Sup Lee, Seung Seok Han

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Figure 6

Overwhelming of the IFN-γ/IL-9 axis in the late phase of VISTA-depleted kidneys.

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Overwhelming of the IFN-γ/IL-9 axis in the late phase of VISTA-depleted ...
(A) Survival rates of NTN-induced WT and Vsir–/– mice (n = 12 per group). Statistical significance for survival was calculated using the Kaplan-Meier method with the log-rank test. (B) Kidney damage markers in WT and Vsir–/– mice that had survived to day 36 after NTN induction. (C) Representative PAS-staining images of kidneys at day 36 after NTN induction. Scale bars: 100 μm (left); 50 μm (right). (D) Glomerular and tubular injury scores at day 36 after NTN induction. (E) Proportions of cytokine-producing T cells evaluated by flow cytometry. (F) Proportions of IFN-γ+ cells in CD4+, CD8+, and other immune cells. (G) Representative plots of kidney sections immunostained for IL-9 and comparison of the IL-9+ area between WT and Vsir–/– kidneys. (H) Representative Masson trichrome plots of kidney sections and comparison between WT and Vsir–/– kidneys. (I) Representative Sirius red plots of kidney sections and comparison between WT and Vsir–/– kidneys. (J) Representative Sirius red plots of kidney sections immunostained for αSMA, and comparison between WT and Vsir–/– kidneys. Data are represented as mean ± SEM (n = 7–12 per group). Scale bars: 100 μm. P values were calculated using an unpaired Student’s t test for 2 groups or ANOVA with Tukey’s test for multiple comparison. *P < 0.05; **P < 0.01; ***P < 0.001. Data represent 2 or 3 independent experiments.