Myelin-phagocytosing macrophages modulate autoreactive T cell proliferation.
Myelin-phagocytosing macrophages modulate autoreactive T cell proliferation.
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DOI：
10.1186/1742-2094-8-85
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发表时间：
2011-07-25
影响因子：
9.3
通讯作者：
Hendriks JJ
中科院分区：
文献类型：
--
作者：
Bogie JF;Stinissen P;Hellings N;Hendriks JJ
多发性硬化症 (MS) 是一种中枢神经系统 (CNS) 的慢性炎症性脱髓鞘疾病，其中巨噬细胞发挥着核心作用。最初，巨噬细胞被认为仅对多发性硬化症有害，但最近的证据表明，巨噬细胞的功能表型在髓磷脂吞噬作用后发生改变。吞噬髓磷脂的巨噬细胞可能会减少炎症，并可能发挥有益的作用。多发性硬化症患者的中枢神经系统引流淋巴结和血管周围间隙中存在含有髓磷脂的巨噬细胞，这表明这些细胞处于发挥免疫调节作用的理想位置。因此，我们在本研究中评估了吞噬髓磷脂的巨噬细胞对淋巴细胞反应性的影响。巯基乙酸引发的大鼠腹膜巨噬细胞负载髓磷脂，并与髓磷脂碱性蛋白（MBP）或卵清蛋白（OVA）反应性淋巴细胞共培养。通过 CFSE 标记测定淋巴细胞增殖。通过向共培养物中添加诱导型一氧化氮合酶抑制剂来评估一氧化氮在调节淋巴细胞增殖中的作用。通过用髓磷脂皮下处理 MBP 和 OVA 免疫的动物来研究体内免疫调节。免疫后9天测定同源抗原特异性淋巴细胞增殖和一氧化氮产生。在这项研究中，我们证明髓磷脂吞噬巨噬细胞以不依赖于抗原的方式抑制 TCR 触发的淋巴细胞增殖。观察到的免疫抑制是由髓磷脂吞噬巨噬细胞与淋巴细胞接触后 NO 产生增加介导的。此外，髓鞘质主要递送至 OVA 免疫动物腘淋巴结中的 CD169+ 巨噬细胞，导致同源抗原特异性增殖减少。与OVA免疫的动物相比，来自MBP免疫的动物的淋巴细胞在用其同源抗原刺激后表现出增加的增殖，表明髓磷脂吞噬巨噬细胞根据周围淋巴细胞的特异性而具有双重作用。总的来说，我们的数据表明髓磷脂吞噬作用会导致巨噬细胞功能改变，从而抑制淋巴细胞增殖。此外，这项研究的结果表明髓磷脂吞噬巨噬细胞在体内发挥双重作用。一方面，它们通过激活髓磷脂反应性淋巴细胞来加剧自身免疫，另一方面，它们通过产生NO来抑制淋巴细胞反应性。
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) in which macrophages play a central role. Initially, macrophages where thought to be merely detrimental in MS, however, recent evidence suggests that their functional phenotype is altered following myelin phagocytosis. Macrophages that have phagocytosed myelin may be less inflammatory and may exert beneficial effects. The presence of myelin-containing macrophages in CNS-draining lymph nodes and perivascular spaces of MS patients suggests that these cells are ideally positioned to exert an immune regulatory role. Therefore we evaluated in this study the effect of myelin-phagocytosing macrophages on lymphocyte reactivity. Thioglycolate-elicited rat peritoneal macrophages were loaded with myelin and cocultured with myelin-basic protein (MBP) or ovalbumin (OVA) reactive lymphocytes. Lymphocyte proliferation was determined by CFSE-labeling. The role of nitric oxide in regulating lymphocyte proliferation was assessed by addition of an inhibitor of inducible nitric oxide synthase to the coculture. In vivo immune regulation was investigated by treating MBP- and OVA-immunized animals subcutaneously with myelin. Cognate antigen specific lymphocyte proliferation and nitric oxide production were determined 9d post-immunization. In this study we demonstrate that myelin-phagocytosing macrophages inhibit TCR-triggered lymphocyte proliferation in an antigen-independent manner. The observed immune suppression is mediated by an increase in NO production by myelin-phagocytosing macrophages upon contact with lymphocytes. Additionally, myelin delivery to primarily CD169+ macrophages in popliteal lymph nodes of OVA-immunized animals results in a reduced cognate antigen specific proliferation. In contrast to OVA-immunized animals, lymphocytes from MBP-immunized animals displayed an increased proliferation after stimulation with their cognate antigen, indicating that myelin-phagocytosing macrophages have dual effects depending on the specificity of surrounding lymphocytes. Collectively our data show that myelin phagocytosis leads to an altered macrophage function that inhibits lymphocyte proliferation. Additionally, results from this study indicate that myelin-phagocytosing macrophages fulfill a dual role in vivo. On one hand they aggravate autoimmunity by activating myelin-reactive lymphocytes and on the other hand they suppress lymphocyte reactivity by producing NO.
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影响因子：
3.3
作者：
Fabriek, BO;Zwernmer, JNP;Castelijns, JA
通讯作者：
Castelijns, JA
影响因子：
3.3
作者：
Cowden, WB;Cullen, FA;Willenborg, DO
通讯作者：
Willenborg, DO
影响因子：
3.3
作者：
Hendriks, Jerome J. A.;Slaets, Helena;Hellings, Niels
通讯作者：
Hellings, Niels
影响因子：
4.4
作者：
Jeon, Sae-Bom;Yoon, Hee Jung;Park, Eun Jung
通讯作者：
Park, Eun Jung
影响因子：
4.4
作者：
Hamilton, Melisa J.;Antignano, Frann;Krystal, Gerald
通讯作者：
Krystal, Gerald