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.
Highlights
Glomerulonephritis is the most common form of glomerular injury, and if severe, it can lead to tubular dysfunction and leave irreversible fibrotic matrix in the interstitium [1, 2]
When the macrophages were categorized into kidney-resident (CD45+Ly6G–CD11bintF4/80hi; termed R1) and kidney-infiltrating (CD45+Ly6G–CD11bhiF4/80int; termed R2) subsets [10], the proportion of R2 macrophages increased after nephrotoxic nephritis (NTN) induction due to infiltration (Figure 1A)
If V-domain Ig suppressor of T cell activation (VISTA) was not expressed in the kidney, immunometabolic changes occurred, such as high oxidative phosphorylation and fatty acid metabolism and IFN-γ overproduction
Summary
Glomerulonephritis is the most common form of glomerular injury, and if severe, it can lead to tubular dysfunction and leave irreversible fibrotic matrix in the interstitium [1, 2]. This pathological process is clinically evident such that heavy proteinuria is a risk factor for chronic kidney disease and end-stage kidney disease [3]. Linkage of pathologies between glomerular and tubulointerstitial compartments may be explainable by the fact that filtered proteins in glomeruli have direct toxic effects on tubules if reabsorbed, and these tubules display altered gene signatures such as apoptosis and produce inflammatory cytokines [4]. How immune cells participate in this linkage during inflammatory or antiinflammatory processes is not yet fully understood
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