Neutrophils Amplify Autoimmune Central Nervous System Infiltrates by Maturing Local APCs
Neutrophils Amplify Autoimmune Central Nervous System Infiltrates by Maturing Local APCs
复制标题
DOI：
10.4049/jimmunol.1202613
复制
发表时间：
2013-11-01
影响因子：
4.4
通讯作者：
Friese, Manuel A.
中科院分区：
文献类型：
--
作者：
Steinbach, Karin;Piedavent, Melanie;Friese, Manuel A.
多发性硬化症被认为是由失调的髓磷脂特异性T细胞反应引起的。然而，炎症性中枢神经系统病变的形成以及不同白细胞亚群在这些病变的形成中所起的作用仍不完全清楚。在本研究中，我们发现，在多发性硬化症，实验性自身免疫性脑脊髓炎小鼠模型中，中性粒细胞是准备中枢神经系统炎症的重要贡献者。临床前单剂量抗体介导的中性粒细胞耗竭延迟了发病，持续耗竭减弱了实验性自身免疫性脑脊髓炎的发展，而髓磷脂特异性T细胞反应的产生不受影响。通过使用各自的敲除小鼠和抑制剂分析，中性粒细胞相关酶如髓过氧化物酶和中性粒细胞弹性酶没有增加中枢神经系统炎症。在体外，浸润中枢神经系统的中性粒细胞分泌促炎分子和成熟的骨髓来源的树突状细胞，这反过来增强了它们重新刺激髓磷脂特异性T细胞的能力。这在体内也得到了反映，在体内，中性粒细胞的消耗特异性地损害了小胶质细胞和巨噬细胞成熟为专业apc，导致早期中枢神经系统炎症扩增减少。因此，在中枢神经系统内，中性粒细胞提供髓系细胞成熟为专业apc所需的局部辅助因子，这是髓鞘特异性T细胞局部再刺激和自身免疫性疾病发展的重要步骤。
Multiple sclerosis is considered to be initiated by a deregulated, myelin-specific T cell response. However, the formation of inflammatory CNS lesions and the contribution of different leukocyte subsets in setting up these lesions are still incompletely understood. In this study, we show that, in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, neutrophil granulocytes are important contributors in preparing CNS inflammation. Preclinical single-dose Ab-mediated depletion of neutrophils delayed the onset and continuous depletion attenuated the development of experimental autoimmune encephalomyelitis, whereas the generation of a myelin-specific T cell response remained unaffected. Neutrophil-related enzymes such as myeloperoxidase and neutrophil elastase did not contribute in mounting CNS inflammation, as analyzed by using respective knockout mice and inhibitors. CNS-infiltrating neutrophils secreted proinflammatory molecules and matured bone marrow-derived dendritic cells in vitro, which in turn enhanced their ability to restimulate myelin-specific T cells. This was mirrored in vivo, in which depletion of neutrophils specifically impaired maturation of microglia and macrophages into professional APCs, resulting in a diminished amplification of early CNS inflammation. Therefore, inside the CNS neutrophils provide local cofactors that are required for the maturation of myeloid cells into professional APCs representing an essential step for the local restimulation of myelin-specific T cells and the development of autoimmune disease.