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.

中文翻译：

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肾脏 VISTA 可预防急性肾小球损伤后 IFN-γ/IL-9 轴介导的肾小管间质纤维化

严重的肾小球损伤最终会导致决定患者预后的肾小管间质纤维化，但连接这些过程的免疫分子仍未确定。本研究探讨了在肾巨噬细胞中组成型表达的 T 细胞活化的 V 域 Ig 抑制因子 (VISTA) 是否在急性抗体介导的肾小球肾炎后的肾小管间质纤维化转化中起保护作用。使用肾毒性血清急性肾小球损伤后，VISTA 缺陷（Vsir–/–) 肾脏比 WT 肾脏遭受的损害更大。当检查间质免疫细胞时，巨噬细胞与浸润的 T 细胞的接触频率增加，T 细胞的免疫代谢特征变为显示高氧化磷酸化和脂肪酸代谢以及 IFN- γ的过量产生。随着更多 IL-9的产生， Vsir–/–实质组织细胞对这种改变的间质免疫细胞环境作出反应，这增加了肾小管间质纤维化。阻断针对 IFN- γ的抗体而 IL-9 在 VISTA 耗尽的条件下保护了上述病理过程。在患有急性肾小球损伤（例如，抗中性粒细胞胞质自身抗体血管炎）的人类样本中，肾小管间质免疫细胞中的高 VISTA 表达与低肾小管间质纤维化和良好预后相关。因此，VISTA 是一种在肾巨噬细胞中表达的前哨蛋白，可在急性抗体介导的肾小球损伤后通过 IFN- γ /IL-9 轴预防肾小管间质纤维化。