Olmes Gregor, Büttner-Herold Maike, Ferrazzi Fulvia, Distel Luitpold, Amann Kerstin, Daniel Christoph
Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Krankenhausstr. 8-10, 91054, Erlangen, Germany.
Institute of Human Genetics, FAU Erlangen-Nürnberg, 91054, Erlangen, Germany.
Arthritis Res Ther. 2016 Apr 18;18:90. doi: 10.1186/s13075-016-0989-y.
The role of macrophages in the pathogenesis of lupus nephritis, in particular their differentiation to a certain subtype (e.g., M1- or M2-like) modulating the inflammatory reaction, is unknown. Here we investigated whether the differentiation in M1- or M2-like macrophages depends on the stage of lupus nephritis and whether this correlates with clinical parameters.
Using immunohistochemical analysis we analyzed renal biopsies from 68 patients with lupus nephritis (ISN/RPS classes II-V) for infiltration with M1-like (iNOS+/CD68+), M2a-like (CD206+/CD68+), M2c-like macrophages (CD163+/CD68+), and FoxP3+ regulatory T-cells. In addition, clinical parameters at the time of renal biopsy, i.e., blood pressure, proteinuria and serum urea were correlated with the macrophage infiltration using the Spearman test.
The mean number of CD68+ macrophages was related to the diagnosed ISN/RPS class, showing the highest macrophage infiltration in biopsies with diffuse class IV and the lowest number in ISN/RPS class V. In all ISN/RPS classes we detected more M2c-like CD163+/CD68+ than M2a-like CD206+/CD68+ cells, while M1-macrophages played only a minor role. Cluster analysis using macrophage subtype numbers in different renal compartments revealed three main clusters showing cluster 1 dominated by class V. Clusters 2 and 3 were dominated by lupus class IV indicating that this class can be further differentiated by its macrophage population. The number of tubulointerstitial FoxP3+ cells correlated with all investigated macrophage subtypes showing the strongest association to numbers of M2a-like macrophages. Kidney function, as assessed by serum creatinine and serum urea, correlated positively with the number of total CD68+, M2a-like and M2c-like macrophages in the tubulointerstitium. In addition, total CD68+ and M2c-like macrophage numbers highly correlated with Austin activity score. Interestingly, in hypertensive lupus patients only the number of M2a-like macrophages was significantly increased compared to biopsies from normotensive lupus patients.
M2-like macrophages are the dominant subpopulation in human lupus nephritis and particularly, M2a subpopulations were associated with disease progression, but their role in disease progression remains unclear.
巨噬细胞在狼疮性肾炎发病机制中的作用，尤其是它们分化为调节炎症反应的特定亚型（如M1样或M2样）的作用尚不清楚。在此，我们研究了M1样或M2样巨噬细胞的分化是否取决于狼疮性肾炎的阶段，以及这是否与临床参数相关。
我们使用免疫组织化学分析，对68例狼疮性肾炎患者（ISN/RPS分级II - V级）的肾活检组织进行分析，检测M1样（iNOS+/CD68+）、M2a样（CD206+/CD68+）、M2c样巨噬细胞（CD163+/CD68+）以及FoxP3+调节性T细胞浸润情况。此外，使用Spearman检验将肾活检时的临床参数，即血压、蛋白尿和血清尿素，与巨噬细胞浸润情况相关联。
CD68+巨噬细胞的平均数量与诊断的ISN/RPS分级相关，在弥漫性IV级活检组织中巨噬细胞浸润最多，而在ISN/RPS V级中数量最少。在所有ISN/RPS分级中，我们检测到的M2c样CD163+/CD68+细胞比M2a样CD206+/CD68+细胞更多，而M1巨噬细胞起的作用较小。使用不同肾区巨噬细胞亚型数量进行聚类分析，发现三个主要聚类，其中聚类1以V级为主。聚类2和3以狼疮IV级为主，表明该分级可根据其巨噬细胞群体进一步区分。肾小管间质中FoxP3+细胞的数量与所有研究的巨噬细胞亚型相关，与M2a样巨噬细胞数量的相关性最强。通过血清肌酐和血清尿素评估的肾功能与肾小管间质中总CD68+、M2a样和M2c样巨噬细胞的数量呈正相关。此外，总CD68+和M2c样巨噬细胞数量与奥斯汀活动评分高度相关。有趣的是，与血压正常的狼疮患者的活检组织相比，高血压狼疮患者中仅M2a样巨噬细胞的数量显著增加。
M2样巨噬细胞是人类狼疮性肾炎中的主要亚群，特别是M2a亚群与疾病进展相关，但其在疾病进展中的作用仍不清楚。
