Department of Nephrology and Rheumatology, University Medical Center Göttingen, 37075 Göttingen, Germany.
Int J Mol Sci. 2023 Jun 25;24(13):10636. doi: 10.3390/ijms241310636.
In systemic lupus erythematosus (SLE), the relevance of non-hematopoietic sources of type I interferon in human autoimmunity has recently been recognized. Particularly, type I interferon production precedes autoimmunity in early skin lesions related to SLE. However, the relevance of intrarenal type I interferon expression has not been shown in lupus nephritis. From transcriptome array datasets, median-centered log mRNA expression levels of IFNα (, , , , , , , , , , , , and ), IFNω (), and IFNβ () in lupus nephritis were extracted specifically from microdissected tubulointerstitial ( = 32) and glomerular compartments ( = 32). We found an association between proteinuria and tubulointerstitial expression of type I interferon ( = 0.0142), while all others were not significantly associated. By contrast, no such correlation was observed between proteinuria and any type I interferon expression in the glomerular compartment in lupus nephritis. Interestingly, there was no difference between female and male patients ( = 0.8237) and no association between type I interferon expression and kidney function or lupus nephritis progression. Finally, we identified distinct molecular signatures involved in transcriptional regulation (GLI protein-regulated transcription, IRF7 activation, and HSF1-dependent transactivation) and receptor signaling (BMP signaling and GPCR ligand binding) in association with tubulointerstitial expression of type I interferon in the kidney. In summary, this transcriptome array-based approach links proteinuria to the tubulointerstitial expression of type I interferon in lupus nephritis. Because type I interferon receptor subunit I antagonism has recently been investigated in active SLE, the current study further emphasizes the role of type I interferons in lupus nephritis and might also be of relevance for mechanistic studies.
在系统性红斑狼疮 (SLE) 中，最近已经认识到 I 型干扰素的非造血来源在人类自身免疫中的相关性。特别是，I 型干扰素的产生先于与 SLE 相关的早期皮肤病变中的自身免疫。然而，在狼疮性肾炎中尚未显示肾内 I 型干扰素表达的相关性。从转录组阵列数据集，提取了狼疮肾炎中微切割的肾小管间质（= 32）和肾小球区室（= 32）中 IFNα（，，，，，，，，，，，和）、IFNω（）和 IFNβ（）的中值中心化 log mRNA 表达水平。我们发现蛋白尿与 I 型干扰素的肾小管间质表达之间存在关联（= 0.0142），而其他均无显著相关性。相比之下，在狼疮肾炎的肾小球区室中，蛋白尿与任何 I 型干扰素的表达均无相关性。有趣的是，女性和男性患者之间没有差异（= 0.8237），并且 I 型干扰素表达与肾功能或狼疮肾炎进展之间没有关联。最后，我们确定了与肾脏中 I 型干扰素表达相关的参与转录调节（GLI 蛋白调节转录、IRF7 激活和 HSF1 依赖性反式激活）和受体信号（BMP 信号和 GPCR 配体结合）的不同分子特征。总之，这种基于转录组阵列的方法将蛋白尿与狼疮肾炎中 I 型干扰素的肾小管间质表达联系起来。由于最近在活动性 SLE 中研究了 I 型干扰素受体亚单位 I 的拮抗作用，本研究进一步强调了 I 型干扰素在狼疮性肾炎中的作用，并且可能对机制研究也具有相关性。
