Inhibition of endogenous activated protein C attenuates experimental autoimmune encephalomyelitis by inducing myeloid-derived suppressor cells.
Inhibition of endogenous activated protein C attenuates experimental autoimmune encephalomyelitis by inducing myeloid-derived suppressor cells.
复制标题
DOI：
10.4049/jimmunol.1202556
复制
发表时间：
2013-10-01
期刊：
影响因子：
--
通讯作者：
Bynoe MS
中科院分区：
文献类型：
--
作者：
Alabanza LM;Esmon NL;Esmon CT;Bynoe MS
活化蛋白C（APC）是一种参与凝血和免疫系统之间相互作用的抗凝剂。APC具有广泛的抗炎作用，通过其调节白细胞功能和赋予血管屏障保护的能力来介导。我们研究了APC对多发性硬化动物模型实验性自身免疫性脑脊髓炎（EAE）发病机制的影响。我们调制APC水平在EAE诱导过程中，通过系统性管理的单克隆抗体对蛋白C/APC（抗PC）的循环。我们最初假设APC的抑制可能导致炎症环境的升高，从而导致EAE发病机制的增加。与该假设相反，用抗PC抗体处理的小鼠表现出减弱的EAE。有趣的是，尽管CNS中疾病严重程度降低且致病性条件最小，但抗PC小鼠在脑中表现出相当大的白细胞浸润，与患有重度EAE的对照小鼠相当。此外，CD 4 + T细胞在抗PC小鼠的外周减少，而各种CD 11b+群体增加，特别是髓源性抑制细胞（MDSC），一个CD 11b+亚群，其特征在于有效的T细胞抑制。来自抗PC小鼠的MDSC表现出T细胞抑制因子的表达增加，并有效地抑制T细胞增殖。总的来说，我们的研究结果表明，APC抑制影响EAE发病机制在多个方面，特别是增加血管屏障通透性，证明了相当大的白细胞浸润在大脑中。此外，APC抑制调节了CD 11b+细胞的功能反应，导致MDSC的扩增和活化增加，MDSC抑制EAE进展所需的CD 4 + T细胞，从而导致减弱的EAE。
Activated protein C (APC) is an anti-coagulant involved in the interactions between the coagulation and immune systems. APC has broad anti-inflammatory effects mediated through its ability to modulate leukocyte function and confer vascular barrier protection. We investigated the influence of APC on the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. We modulated APC levels in the circulation during EAE induction through systemic administration of a monoclonal antibody against protein C/APC (anti-PC). We initially hypothesized that inhibition of APC may result in a heightened inflammatory environment leading to increased EAE pathogenesis. Contrary to this hypothesis, mice treated with anti-PC antibody exhibited attenuated EAE. Interestingly, despite reduced disease severity and minimal pathogenic conditions in the CNS, anti-PC mice exhibited considerable leukocyte infiltration in the brain, comparable to control mice with severe EAE. Furthermore, CD4+ T-cells were diminished in the periphery of anti-PC mice while various CD11b+ populations were increased, notably the myeloid-derived suppressor cells (MDSC), a CD11b+ subset characterized as potent T-cell suppressors. MDSCs from anti-PC mice exhibited increased expression of T-cell-suppressive factors and effectively inhibited T-cell proliferation. Overall, our findings show that APC inhibition affected EAE pathogenesis at multiple fronts; specifically, increasing vascular barrier permeability, as evidenced by considerable leukocyte infiltration in the brain. APC inhibition, additionally, modulated the functional responses of CD11b+ cells leading to the expansion and increased activation of MDSCs, which are suppressive to the CD4+ T-cells required for EAE progression, thereby resulting in attenuated EAE.
登录
查看更多内容
影响因子：
4.8
作者：
Joyce, DE;Gelbert, L;Grinnell, BW
通讯作者：
Grinnell, BW
影响因子：
9
作者：
Esmon, Charles T.
通讯作者：
Esmon, Charles T.
影响因子：
3.3
作者：
KOH, CS;GAUSAS, J;PATERSON, PY
通讯作者：
PATERSON, PY
影响因子：
15.9
作者：
Cao, Chunzhang;Gao, Yamei;Zhang, Li
通讯作者：
Zhang, Li
影响因子：
4.4
作者：
Inaba, Y;Ichikawa, M;Koh, CS
通讯作者：
Koh, CS