Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
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

  • Text
  • PDF
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 7

Confirmation of the IFN-γ/IL-9 fibrosis axis.

Options: View larger image (or click on image) Download as PowerPoint
Confirmation of the IFN-γ/IL-9 fibrosis axis.
(A) Kidney damage markers ...
(A) Kidney damage markers in vehicle- and rmIFN-γ-treated WT kidneys. (B) Representative plots of kidney sections immunostained for IL-9 and comparison of the IL-9+ area between vehicle- and rmIFN-γ–treated kidneys. (C) Kidney damage markers in control antibody- and anti–IFN-γ antibody–treated Vsir–/– kidneys. (D) Representative plots of kidney sections immunostained for IL-9 and comparison of the IL-9+ area between control antibody- and anti–IFN-γ antibody–treated kidneys. (E) Kidney damage markers in NTN-induced Rag1–/– mice with adoptive transfer of naive CD8+ T cells from WT and Ifng–/– mice. (F) Representative plots of kidney sections immunostained for IL-9 and comparison of the IL-9+ area in NTN-induced Rag1–/– kidneys between WT mouse-derived and Ifng–/– mouse–derived naive CD8+ T cell transfer. (G) Kidney damage markers in vehicle- and rmIL-9–treated WT kidneys. (H) Representative plots of kidney sections immunostained for Sirius red and comparison of the Sirius red+ area between vehicle- and rmIL-9-treated WT kidneys. (I) Kidney damage markers in control antibody- and anti–IL-9 antibody–treated Vsir–/– kidneys. (J) Representative plots of kidney sections immunostained for Sirius red and comparison of the Sirius red+ area between control antibody– and anti–IL-9 antibody–treated Vsir–/– kidneys. Scale bars: 100 μm. (K) Representative PAS staining images of control antibody- and anti–IL-9 antibody–treated Vsir–/– kidneys. Scale bars: 100 μm. (L) Glomerular and tubular injury scores in control antibody– and anti–IL-9 antibody–treated Vsir–/– kidneys. (M) Proportions of T cell subsets in control antibody– and anti–IL-9 antibody–treated Vsir–/– kidneys. Data are represented as mean ± SEM (n = 4–7 per group). P values were calculated using an unpaired Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001. Data represent 2 or 3 independent experiments.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts