Glucocorticoid Therapy of Multiple Sclerosis Patients Induces Anti-inflammatory Polarization and Increased Chemotaxis of Monocytes
Glucocorticoid Therapy of Multiple Sclerosis Patients Induces Anti-inflammatory Polarization and Increased Chemotaxis of Monocytes
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DOI：
10.3389/fimmu.2019.01200
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发表时间：
2019-05-29
影响因子：
7.3
通讯作者：
Luehder, Fred
中科院分区：
文献类型：
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作者：
Fischer, Henrike J.;Finck, Tobias L. K.;Luehder, Fred
多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 自身免疫性疾病，其特征是单核细胞浸润到中枢神经系统并随后引起脑部炎症。单核细胞与疾病发病机制有关，不仅因为它们作为参与致脑炎 T 细胞局部再激活的潜在抗原呈递细胞的功能，而且还因为其独立效应功能导致结构损伤和疾病进展。然而，单核细胞也有有益的作用，因为它们可以发挥抗炎活性并促进组织修复。糖皮质激素 (GC) 广泛用于治疗多发性硬化症患者的急性复发。它们作用于多种细胞类型，但其确切的作用机制（包括对单核细胞功能的调节）尚不完全清楚。在这里，我们研究了治疗相关的 GC 甲基泼尼松龙 (MP) 对健康个体和多发性硬化症患者的单核细胞的体外和体内影响。与健康个体相比，多发性硬化症患者血液中的单核细胞成分有所不同，但仅受 MP 治疗的轻微影响。相比之下，如基因表达谱的改变所揭示的，MP的应用在体外和体内引起了向抗炎单核细胞表型的显着转变。与健康个体相比，多发性硬化症患者的单核细胞对 CCL2、CCL5 和 CX3CL1 的趋化性增加，并且通过 MP 脉冲治疗进一步增强。这两种迁移促进作用在急性复发的多发性硬化症患者中比在疾病进展的患者中更为明显。有趣的是，促迁移 GC 效应与趋化因子受体水平无关，如 CCR2 获得的结果所示。总的来说，我们的研究结果表明，GC 使单核细胞极化为抗炎表型，并增强它们向发炎中枢神经系统的迁移，赋予它们抑制致病性免疫反应的能力。
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by the infiltration of mononuclear cells into the CNS and a subsequent inflammation of the brain. Monocytes are implicated in disease pathogenesis not only in their function as potential antigen-presenting cells involved in the local reactivation of encephalitogenic T cells but also by independent effector functions contributing to structural damage and disease progression. However, monocytes also have beneficial effects as they can exert anti-inflammatory activity and promote tissue repair. Glucocorticoids (GCs) are widely used to treat acute relapses in MS patients. They act on a variety of cell types but their exact mechanisms of action including their modulation of monocyte function are not fully understood. Here we investigated effects of the therapeutically relevant GC methylprednisolone (MP) on monocytes from healthy individuals and MS patients in vitro and in vivo. The monocyte composition in the blood was different in MS patients compared to healthy individuals, but it was only marginally affected by MP treatment. In contrast, application of MP caused a marked shift toward an anti-inflammatory monocyte phenotype in vitro and in vivo as revealed by an altered gene expression profile. Chemotaxis of monocytes toward CCL2, CCL5, and CX3CL1 was increased in MS patients compared to healthy individuals and further enhanced by MP pulse therapy. Both of these migration-promoting effects were more pronounced in MS patients with an acute relapse than in those with a progressive disease. Interestingly, the pro-migratory GC effect was independent of chemokine receptor levels as exemplified by results obtained for CCR2. Collectively, our findings suggest that GCs polarize monocytes toward an anti-inflammatory phenotype and enhance their migration into the inflamed CNS, endowing them with the capacity to suppress the pathogenic immune response.