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.
View: Text | PDF
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

×

Figure 1

VISTA expression in the NTN model.

Options: View larger image (or click on image) Download as PowerPoint
VISTA expression in the NTN model. (A) Representative flow cytometry plo...
(A) Representative flow cytometry plot of R1 and R2 macrophages. Cells were gated from DAPI–CD45+Ly6G– subset. Proportions of R1 and R2 macrophages at day 8 after NTN induction (n = 7 per group). (B) UMAP plots of 86,254 cells pooled from 3 sources with C57BL/6 mice. PT, proximal tubule; DL-tAL, descending limb and thin ascending limb of loop of Henle; TAL, thick ascending limb of loop of Henle; DCT, distal convoluted tubule; PC, principal cell of collecting duct; IC, intercalated cell of collecting duct; ENDO, endothelial cell; PERI, pericyte; PODO, podocyte; Uro, urothelium; EC, erythrocyte. (C) Dot plots to identify clusters of parenchymal tissue cells (left) and immune cells (right). (D) Violin and dot plots for the expression levels of the Vsir gene in clusters. (E) Expression of VISTA protein in R1 and R2 macrophages at day 8 after NTN induction (n = 7 per group). A representative flow cytometry plot of VISTA is shown. (F) Representative image of kidney sections immunostained for DAPI, VISTA, and F4/80. Upper and lower images represent before and after NTN induction, respectively. Scale bar: 100 μm. (G) Expression of VISTA protein in other immune cells, such as CD4+ T (CD45+CD3+CD4+), CD8+ T (CD45+CD3+CD8+), double-negative (DN) T (CD45+CD3+CD4–CD8–), B (CD45+CD19+), and NK (CD45+CD3–NK1.1+) cells (n = 4 per group). A representative flow cytometry plot of VISTA after NTN induction is shown. Data are represented as mean ± SEM. P values were calculated using an unpaired Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001. Data represent at least 3 independent experiments.