Distinct Modulation of Human Myeloid and Plasmacytoid Dendritic Cells by Anandamide in Multiple Sclerosis
Distinct Modulation of Human Myeloid and Plasmacytoid Dendritic Cells by Anandamide in Multiple Sclerosis
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DOI：
10.1002/ana.23875
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发表时间：
2013-05-01
影响因子：
11.2
通讯作者：
Maccarrone, Mauro
中科院分区：
文献类型：
--
作者：
Chiurchiu, Valerio;Cencioni, Maria Teresa;Maccarrone, Mauro
目的 多发性硬化症 (MS) 的免疫发病机制一直被认为是由慢性激活和自身反应性 Th-1 和 Th-17 细胞驱动的。最近，树突状细胞（DC）也被认为对抗原传播和适应性免疫的成熟有显着贡献，并且与疾病进展和恶化有关。然而，DC 在 MS 发病机制中的作用仍知之甚少。方法 我们在体外刺激 Toll 样受体 7/8 后，比较了健康受试者和 MS 患者中髓样 DCs (mDCs) 和浆细胞样 DCs (pDCs) 产生的细胞因子水平。我们还评估了主要内源性大麻素 anandamide (AEA) 在这些 DC 亚群中的作用，并将细胞因子水平与内源性大麻素系统缺陷相关。结果 与健康受试者相比，从 MS 患者获得的 mDC 产生较高水平的白细胞介素 12 和白细胞介素 6，而 pDC 产生较低水平的干扰素。 AEA 显着抑制健康 mDC 和 pDC 的细胞因子产生，以及它们诱导 Th-1 和 Th-17 谱系的能力。此外，我们发现在 MS 中，只有 pDC 对 AEA 诱导的细胞因子抑制缺乏反应。一致地，该特定细胞亚群表达较高水平的 anandamide 水解酶脂肪酸酰胺水解酶 (FAAH)。解释我们的数据揭示了 AEA 在 MS 患者的 mDC 和 pDC 中具有独特的免疫调节作用，这可能反映了 FAAH 表达的改变，从而为合理设计针对特定细胞亚群的新型内源性大麻素免疫治疗药物奠定了基础。
Objective The immunopathogenesis of multiple sclerosis (MS) has always been thought to be driven by chronically activated and autoreactive Th-1 and Th-17 cells. Recently, dendritic cells (DCs) have also been thought to significantly contribute to antigenic spread and to maturation of adaptive immunity, and have been linked with disease progression and exacerbation. However, the role of DCs in MS pathogenesis remains poorly understood. Methods We compared the level of cytokine production by myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in healthy subjects and MS patients, following in vitro stimulation of Toll-like receptors 7/8. We also evaluated the effect of the main endocannabinoid, anandamide (AEA), in these DC subsets and correlated cytokine levels with defects in the endocannabinoid system. Results mDCs obtained from MS patients produce higher levels of interleukin-12 and interleukin-6, whereas pDCs account for lower levels of interferon- compared to healthy subjects. AEA significantly inhibited cytokine production from healthy mDCs and pDCs, as well as their ability to induce Th-1 and Th-17 lineages. Moreover, we found that in MS only pDCs lack responsiveness to cytokine inhibition induced by AEA. Consistently, this specific cell subset expresses higher levels of the anandamide hydrolase fatty acid amide hydrolase (FAAH). Interpretation Our data disclose a distinct immunomodulatory effect of AEA in mDCs and pDCs from MS patients, which may reflect an alteration of the expression of FAAH, thus forming the basis for the rational design of new endocannabinoid-based immunotherapeutic agents targeting a specific cell subset.