Modulation of P2X7 Receptor during Inflammation in Multiple Sclerosis.
Modulation of P2X7 Receptor during Inflammation in Multiple Sclerosis.
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DOI：
10.3389/fimmu.2017.01529
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发表时间：
2017
影响因子：
7.3
通讯作者：
Volonté C
中科院分区：
文献类型：
--
作者：
Amadio S;Parisi C;Piras E;Fabbrizio P;Apolloni S;Montilli C;Luchetti S;Ruggieri S;Gasperini C;Laghi-Pasini F;Battistini L;Volonté C
多发性硬化症(MS)的特征是巨噬细胞聚集和炎症渗入中枢神经系统，导致脱髓鞘。由于已知嘌呤能P2X7受体(P2X7R)在造血系和神经系统的细胞上大量表达，我们进一步研究了其在MS和实验性自身免疫性脑脊髓炎条件下的表型表达。应用定量逆转录聚合酶链式反应和流式细胞术分析了缓解期和缓解期MS患者外周血单个核细胞中P2X7R的表达。人单核细胞也在体外用促炎刺激如脂多糖或P2X7R优先激动剂2‘(3’)-O-(4苯甲酰基苯甲酰基)腺苷5‘-三磷酸激发，然后评估P2X7R蛋白的表达。最后，通过免疫组织化学和免疫荧光共聚焦分析，我们检测了继发性进展性多发性硬化症患者额叶皮质中P2X7R的表达。我们证实，在疾病的急性期，从MS捐献者分离的外周血单核细胞上存在并抑制了P2X7R，而且在体外促炎刺激后，它在人单核细胞上表达下调。而继发性进展性MS患者额叶皮质星形胶质细胞上的P2X7R表达上调，伴随着单核细胞趋化蛋白-1趋化因子，而小胶质/巨噬细胞或少突胶质细胞则完全不表达，尽管存在炎症情况。我们的结果提示，抑制单核细胞的P2X7R和上调星形胶质细胞的表达可能有助于维持MS的炎症机制。通过对P2X7R动力学的进一步了解，并确定P2X7R是一种潜在的疾病标志物，我们希望对MS的分子通路有更深入的了解。
Multiple sclerosis (MS) is characterized by macrophage accumulation and inflammatory infiltrates into the CNS contributing to demyelination. Because purinergic P2X7 receptor (P2X7R) is known to be abundantly expressed on cells of the hematopoietic lineage and of the nervous system, we further investigated its phenotypic expression in MS and experimental autoimmune encephalomyelitis conditions. By quantitative reverse transcription polymerase chain reaction and flow cytometry, we analyzed the P2X7R expression in human mononuclear cells of peripheral blood from stable and acute relapsing-remitting MS phases. Human monocytes were also challenged in vitro with pro-inflammatory stimuli such as the lipopolysaccharide, or the P2X7R preferential agonist 2′(3′)-O-(4 Benzoylbenzoyl)adenosine 5′-triphosphate, before evaluating P2X7R protein expression. Finally, by immunohistochemistry and immunofluorescence confocal analysis, we investigated the P2X7R expression in frontal cortex from secondary progressive MS cases. We demonstrated that P2X7R is present and inhibited on peripheral monocytes isolated from MS donors during the acute phase of the disease, moreover it is down-regulated in human monocytes after pro-inflammatory stimulation in vitro. P2X7R is instead up-regulated on astrocytes in the parenchyma of frontal cortex from secondary progressive MS patients, concomitantly with monocyte chemoattractant protein-1 chemokine, while totally absent from microglia/macrophages or oligodendrocytes, despite the occurrence of inflammatory conditions. Our results suggest that inhibition of P2X7R on monocytes and up-regulation in astrocytes might contribute to sustain inflammatory mechanisms in MS. By acquiring further knowledge about P2X7R dynamics and identifying P2X7R as a potential marker for the disease, we expect to gain insights into the molecular pathways of MS.