| Autor: |
Kim MG; Department of Biomedical Sciences., Yun D; Department of Biomedical Sciences.; Department of Internal Medicine., Kang CL; Department of Biomedical Sciences.; Department of Internal Medicine., Hong M; Department of Biomedical Sciences.; Department of Internal Medicine., Hwang J; Department of Biomedical Sciences.; Department of Internal Medicine., Moon KC; Department of Pathology, and., Jeong CW; Department of Urology, Seoul National University College of Medicine, Seoul, Korea., Kwak C; Department of Urology, Seoul National University College of Medicine, Seoul, Korea., Kim DK; Department of Internal Medicine., Oh KH; Department of Internal Medicine., Joo KW; Department of Internal Medicine., Kim YS; Department of Biomedical Sciences.; Department of Internal Medicine., Lee DS; Department of Biomedical Sciences.; Department of Internal Medicine., Han SS; Department of Internal Medicine. |
| Abstrakt: |
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. |
