Novartis Institutes for Biomedical Research, Basel, Switzerland.
Institute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland.
JCI Insight. 2020 Feb 13;5(3):130651. doi: 10.1172/jci.insight.130651.
Acute kidney injury (AKI) and chronic kidney diseases are associated with high mortality and morbidity. Although the underlying mechanisms determining the transition from acute to chronic injury are not completely understood, immune-mediated processes are critical in renal injury. We have performed a comparison of 2 mouse models leading to either kidney regeneration or fibrosis. Using global gene expression profiling we could identify immune-related pathways accounting for the majority of the observed transcriptional changes during fibrosis. Unbiased examination of the immune cell composition, using single-cell RNA sequencing, revealed major changes in tissue-resident macrophages and T cells. Following injury, there was a marked increase in tissue-resident IL-33R+ and IL-2Ra+ regulatory T cells (Tregs). Expansion of this population before injury protected the kidney from injury and fibrosis. Transcriptional profiling of Tregs showed a differential upregulation of regenerative and proangiogenic pathways during regeneration, whereas in the fibrotic environment they expressed markers of hyperactivation and fibrosis. Our data point to a hitherto underappreciated plasticity in Treg function within the same tissue, dictated by environmental cues. Overall, we provide a detailed cellular and molecular characterization of the immunological changes during kidney injury, regeneration, and fibrosis.
急性肾损伤 (AKI) 和慢性肾脏病与高死亡率和高发病率相关。尽管决定急性损伤向慢性损伤转变的潜在机制尚不完全清楚，但免疫介导的过程在肾损伤中至关重要。我们比较了两种导致肾脏再生或纤维化的小鼠模型。通过全基因表达谱分析，我们可以确定免疫相关途径，这些途径解释了纤维化过程中观察到的大多数转录变化。使用单细胞 RNA 测序对免疫细胞组成进行无偏分析，揭示了组织驻留巨噬细胞和 T 细胞的主要变化。损伤后，组织驻留的 IL-33R+和 IL-2Ra+调节性 T 细胞 (Treg) 明显增加。损伤前该群体的扩张可保护肾脏免受损伤和纤维化。Treg 的转录谱显示，在再生过程中，再生和促血管生成途径的上调存在差异，而在纤维化环境中，它们表达了过度激活和纤维化的标志物。我们的数据表明，在相同组织中，Treg 功能具有迄今为止尚未被充分认识的可塑性，这取决于环境线索。总的来说，我们提供了在肾脏损伤、再生和纤维化过程中免疫变化的详细细胞和分子特征。
