Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, Hammersmith Hospital, London, UK.
Nephrology and Dialysis Unit, Ospedale di Circolo e Fondazione Macchi, ASST-Settelaghi, Varese, Italy.
Rheumatology (Oxford). 2022 Feb 2;61(2):834-845. doi: 10.1093/rheumatology/keab413.
The pro-inflammatory activities of the calgranulins and HMGB1 can be counteracted by sRAGE, the soluble form of their shared receptor. To understand the role of these molecules in AAV and their potential as therapeutic targets we have studied (i) the relationship between these DAMPS and disease activity; (ii) the expression of RAGE and sRAGE in biopsy tissue and peripheral blood; and (iii) the effect of these molecules on ANCA-mediated cytokine production.
We examined circulating levels of calgranulins (S100A8/A9 and S100A12), HMGB1 and sRAGE by ELISA. RAGE was examined in AAV kidney and lung biopsies by immunohistochemistry and RAGE expression was monitored in peripheral blood by qPCR. In vitro, the effect of co-stimulating PBMC with ANCA and S100A8/A9 on cytokine production was studied by ELISA.
We found significantly raised levels of calgranulins and HMGB1 in active AAV regardless of clinical phenotype (PR3+/MPO+ AAV). Levels of calgranulins showed significant correlations with each other. RAGE protein and message was raised in peripheral blood and in cells infiltrating kidney and lung biopsy tissue, while sRAGE was lowered. Furthermore, ANCA-mediated production of IL-8 from PBMC was significantly enhanced by the presence of S100A8/A9 in a RAGE/TLR4-dependent manner.
Raised circulating calgranulins provide a good marker of disease activity in AAV and are unlikely to be counteracted by sRAGE. Increased RAGE expression in AAV indicates receptor stimulation in active disease that may exacerbate ANCA-induced cytokine production. Targeting the RAGE pathway may provide a useful therapeutic approach in AAV.
钙粒蛋白和高迁移率族蛋白 B1 的促炎活性可以被它们共同受体的可溶性形式 sRAGE 抵消。为了了解这些分子在抗中性粒细胞胞质抗体相关性血管炎（AAV）中的作用及其作为治疗靶点的潜力，我们研究了：（i）这些 DAMPs 与疾病活动之间的关系；（ii）活检组织和外周血中 RAGE 和 sRAGE 的表达；（iii）这些分子对 ANCA 介导的细胞因子产生的影响。
我们通过 ELISA 检测了循环中钙粒蛋白（S100A8/A9 和 S100A12）、HMGB1 和 sRAGE 的水平。通过免疫组织化学检测 AAV 肾脏和肺部活检组织中的 RAGE，通过 qPCR 监测外周血中的 RAGE 表达。在体外，通过 ELISA 研究了 ANCA 和 S100A8/A9 共同刺激 PBMC 对细胞因子产生的影响。
我们发现，无论临床表型（PR3+/MPO+ AAV）如何，活动期 AAV 中钙粒蛋白和 HMGB1 的水平均显著升高。钙粒蛋白水平之间存在显著相关性。外周血中 RAGE 蛋白和 mRNA 升高，肾脏和肺部活检组织中浸润细胞升高，而 sRAGE 降低。此外，S100A8/A9 以 RAGE/TLR4 依赖的方式显著增强了 ANCA 介导的 PBMC 中 IL-8 的产生。
循环中钙粒蛋白的升高为 AAV 疾病活动提供了一个良好的标志物，且不太可能被 sRAGE 抵消。AAV 中 RAGE 表达的增加表明在活动期疾病中存在受体刺激，这可能加剧 ANCA 诱导的细胞因子产生。靶向 RAGE 途径可能为 AAV 提供一种有用的治疗方法。
