Mendes-Frias Ana, Santos-Lima Bruno, Furtado Danielle Zildeana Sousa, Ruperez Francisco J, Assunção Nilson Antonio, Matias Maria João, Gomes Vânia, Gaifem Joana, Barbas Coral, Castro António Gil, Capela Carlos, Silvestre Ricardo
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
ICVS/3B's - PT Government Associate Laboratory, Braga, Guimarães, Portugal.
J Transl Autoimmun. 2020 May 11;3:100056. doi: 10.1016/j.jtauto.2020.100056. eCollection 2020.
Behçet's disease (BD) is a relapsing, multisystem and inflammatory condition characterized by systemic vasculitis of small and large vessels. Although the etiopathogenesis of BD remains unknown, immune-mediated mechanisms play a major role in the development of the disease. BD patients present leukocyte infiltration in the mucocutaneous lesions as well as neutrophil hyperactivation. In contrast to neutrophils, whose involvement in the pathogenesis of BD has been extensively studied, the biology of monocytes during BD is less well known. In this study, we analyzed the phenotype and function of circulating monocytes of 38 BD patients from Hospital of Braga. In addition, we evaluated the impact of inflammatory and metabolomic plasma environment on monocyte biology. We observed a worsening of mitochondrial function, with lower mitochondrial mass and increased ROS production, on circulating monocytes of BD patients. Incubation of monocytes from healthy donors with the plasma of BD patients mimicked the observed phenotype, strongly suggesting the involvement of serum mediators. BD patients, regardless of their symptoms, had higher serum pro-inflammatory TNF-α and IP-10 levels and IL-1β/IL-1RA ratio. Untargeted metabolomic analysis identified a dysregulation of glycerophospholipid metabolism on BD patients, where a significant reduction of phospholipids was observed concomitantly with an increase of lysophospholipids and fatty acids. These observations converged to an enhanced phospholipase A2 (PLA) activation. Indeed, inhibition of PLA with dexamethasone or the downstream cyclooxygenase (COX) enzyme with ibuprofen was able to significantly revert the mitochondrial dysfunction observed on monocytes of BD patients. Our results show that the plasma inflammatory environment coupled with a dysregulation of glycerophospholipid metabolism in BD patients contribute to a dysfunction of circulating monocytes.
白塞病（BD）是一种复发性、多系统炎症性疾病，其特征为大小血管的系统性血管炎。尽管BD的病因发病机制尚不清楚，但免疫介导机制在该疾病的发展中起主要作用。BD患者在黏膜皮肤病变处有白细胞浸润以及中性粒细胞过度活化。与中性粒细胞不同，中性粒细胞在BD发病机制中的作用已得到广泛研究，而BD期间单核细胞的生物学特性鲜为人知。在本研究中，我们分析了来自布拉加医院的38例BD患者循环单核细胞的表型和功能。此外，我们评估了炎症和代谢组学血浆环境对单核细胞生物学的影响。我们观察到BD患者循环单核细胞的线粒体功能恶化，线粒体质量降低且活性氧生成增加。用BD患者的血浆孵育健康供体的单核细胞可模拟观察到的表型，强烈提示血清介质的参与。BD患者无论有无症状，其血清促炎细胞因子TNF-α和IP-10水平以及IL-1β/IL-1RA比值均较高。非靶向代谢组学分析发现BD患者甘油磷脂代谢失调，观察到磷脂显著减少，同时溶血磷脂和脂肪酸增加。这些观察结果都指向磷脂酶A2（PLA）的激活增强。事实上，用地塞米松抑制PLA或用布洛芬抑制下游环氧化酶（COX）能够显著逆转BD患者单核细胞中观察到的线粒体功能障碍。我们的结果表明，BD患者血浆炎症环境与甘油磷脂代谢失调共同导致循环单核细胞功能障碍。
