Department of Internal Medicine, Section of Nephrology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; Amsterdam Institute for Infection and Immunity, Inflammatory Diseases, Amsterdam, the Netherlands.
Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands; Department of Experimental Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
Atherosclerosis. 2024 Oct;397:118559. doi: 10.1016/j.atherosclerosis.2024.118559. Epub 2024 Aug 10.
Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) is associated with an increased cardiovascular risk, particularly the myeloperoxidase AAV serotype (MPO-AAV). Distinct alterations in monocyte phenotypes may cause accelerated atherosclerotic disease in AAV.
A cohort including 43 AAV patients and 19 healthy controls was included for downstream analyses. Extensive phenotyping of monocytes and monocyte-derived macrophages was performed using bulk RNA-sequencing and flow cytometry. An in vitro transendothelial migration assay reflecting intrinsic adhesive and migratory capacities of monocytes was employed. Subsequent sub-analyses were performed to investigate differences between serological subtypes.
Monocyte subset analysis showed increased classical monocytes during active disease, whereas non-classical monocytes were decreased compared to healthy controls (HC). RNA-sequencing revealed upregulation of distinct inflammatory pathways and lipid metabolism-related markers in monocytes of active AAV patients. No differences were detected in the intrinsic monocyte adhesion and migration capacity. Compared to proteinase-3(PR3)-AAV, monocytes of MPO-AAV patients in remission expressed genes related to inflammation, coagulation, platelet-binding and interferon signalling, whereas the expression of chemokine receptors indicative of acute inflammation and monocyte extravasation (i.e., CCR2 and CCR5) was increased in monocytes of PR3-AAV patients. During active disease, PR3-AAV was linked with elevated serum CRP and increased platelet counts compared to MPO-AAV.
These findings highlight changes in monocyte subset composition and activation, but not in the intrinsic migration capacity of AAV monocytes. MPO-AAV monocytes are associated with sustained upregulation of inflammatory genes, whereas PR3-AAV monocytes exhibit chemokine receptor upregulation. These molecular changes may play a role in elevating cardiovascular risk as well as in the underlying pathophysiology of AAV.
抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）与心血管风险增加相关，尤其是髓过氧化物酶 AAV 血清型（MPO-AAV）。单核细胞表型的明显改变可能导致 AAV 患者加速动脉粥样硬化疾病的发生。
本研究纳入了 43 名 AAV 患者和 19 名健康对照者进行下游分析。使用批量 RNA 测序和流式细胞术对单核细胞及其衍生的巨噬细胞进行了广泛的表型分析。采用体外跨内皮迁移实验来反映单核细胞的固有黏附和迁移能力。随后进行了亚组分析以研究血清学亚型之间的差异。
单核细胞亚群分析显示，在活动期疾病中经典单核细胞增加，而非经典单核细胞与健康对照组（HC）相比减少。RNA 测序显示，活动期 AAV 患者的单核细胞中存在不同的炎症途径和脂质代谢相关标志物的上调。在固有单核细胞黏附和迁移能力方面未发现差异。与蛋白酶 3（PR3）-AAV 相比，缓解期 MPO-AAV 患者的单核细胞表达与炎症、凝血、血小板结合和干扰素信号相关的基因，而 PR3-AAV 患者的单核细胞中与急性炎症和单核细胞渗出相关的趋化因子受体（即 CCR2 和 CCR5）表达增加。在活动期疾病中，PR3-AAV 与 CRP 血清水平升高和血小板计数增加相关，而 MPO-AAV 则无此相关性。
这些发现强调了 AAV 单核细胞亚群组成和激活的变化，但固有迁移能力没有变化。MPO-AAV 单核细胞与持续上调的炎症基因相关，而 PR3-AAV 单核细胞则表现出趋化因子受体的上调。这些分子变化可能在升高心血管风险以及 AAV 的潜在病理生理学中发挥作用。
