Department of Dermatology, University Hospital Heidelberg, Germany.
Institute of Immunology, Medical Faculty, TU Dresden, Dresden, Germany; National Center for Tumor Diseases, University Hospital Carl Gustav Carus, TU Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Center for Regenerative Therapies Dresden (CRTD), Medical Faculty, TU Dresden, Dresden, Germany.
J Dermatol Sci. 2017 Sep;87(3):278-284. doi: 10.1016/j.jdermsci.2017.06.016. Epub 2017 Jun 24.
The fumaric acid ester (FAE) dimethylfumarate (DMF) is a small molecule immunomodulator successfully used for the treatment of psoriasis and multiple sclerosis (MS). DMF is thought to inhibit pathogenic immune responses with Th17/Th1T cells, and IL-23/IL-12 producing dendritic cells (DCs). 6-sulfo LacNAc expressing dendritic cells (slanDCs) are a human pro-inflammatory cell type found frequently among the infiltrating leukocytes in skin lesions of psoriasis and brain lesions of MS.
To explore the influence of DMF on functional properties and cell signaling pathways of slanDCs.
In the context of slanDCs we studied the role of DMF in modulating cell migration, phenotypic maturation, cytokine production, cell signaling and T cell stimulation.
Initially, we observed the reduction of slanDCs numbers in psoriasis skin lesions of FAE treated patients. Studying whether DMF controls the migratory capacity of slanDCs to chemotactic factors expressed in psoriasis we observed an inhibition of the CX3CL1 and C5a depedent cell migration. DMF also attenuated the rapid spontaneous phenotypic maturation of slanDCs, as judged by a reduced CD80, CD86, CD83 and HLA-DR expression. In addition, we observed a DMF-dependent decrease of IL-23, IL-12, TNF-α and IL-10 secretion, and noticed a reduced capacity to stimulate Th17/Th1 responses. DMF targeted in slanDCs different intracellular cell signaling pathways including NFκB, STAT1 and HO-1.
With this study we identify a frequent pro-inflammatory cell type found in psoriasis and MS as a relevant target for the therapeutic immunomodulatory effects of DMF.
富马酸酯（FAE）二甲酯（DMF）是一种小分子免疫调节剂，成功用于治疗银屑病和多发性硬化症（MS）。DMF 被认为通过 Th17/Th1T 细胞和 IL-23/IL-12 产生树突状细胞（DC）来抑制致病性免疫反应。6-硫酸乳糖胺表达的树突状细胞（slanDCs）是一种人类炎症细胞类型，在银屑病皮损和 MS 脑病变中浸润的白细胞中经常发现。
探讨 DMF 对 slanDCs 功能特性和细胞信号通路的影响。
在 slanDCs 的背景下，我们研究了 DMF 在调节细胞迁移、表型成熟、细胞因子产生、细胞信号转导和 T 细胞刺激中的作用。
最初，我们观察到 FAE 治疗的患者银屑病皮损中 slanDCs 的数量减少。研究 DMF 是否控制 slanDCs 向银屑病中表达的趋化因子的迁移能力时，我们观察到 CX3CL1 和 C5a 依赖性细胞迁移受到抑制。DMF 还减弱了 slanDCs 的快速自发表型成熟，表现为 CD80、CD86、CD83 和 HLA-DR 表达减少。此外，我们观察到 DMF 依赖性 IL-23、IL-12、TNF-α和 IL-10 分泌减少，并注意到刺激 Th17/Th1 反应的能力降低。DMF 在 slanDCs 中靶向不同的细胞内信号通路，包括 NFκB、STAT1 和 HO-1。
通过这项研究，我们确定了一种在银屑病和 MS 中发现的常见炎症细胞类型，作为 DMF 治疗免疫调节作用的相关靶点。
