Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853;
J Immunol. 2013 Oct 1;191(7):3764-77. doi: 10.4049/jimmunol.1202556. Epub 2013 Aug 30.
Activated protein C (PC) is an anticoagulant involved in the interactions between the coagulation and immune systems. Activated PC has broad anti-inflammatory effects that are mediated through its ability to modulate leukocyte function and confer vascular barrier protection. We investigated the influence of activated PC on the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. We modulated activated PC levels in the circulation during EAE induction through systemic administration of a mAb against PC/activated PC (anti-PC). We initially hypothesized that inhibition of activated PC may result in a heightened inflammatory environment, leading to increased EAE pathogenesis. Contrary to this hypothesis, mice treated with anti-PC Ab (anti-PC mice) 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, whereas various CD11b(+) populations were increased, notably the myeloid-derived suppressor cells (MDSCs), 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 activated PC inhibition affected EAE pathogenesis at multiple fronts, specifically increasing vascular barrier permeability, as evidenced by considerable leukocyte infiltration in the brain. Additionally, inhibition of activated PC 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.
活化蛋白 C（PC）是一种参与凝血和免疫系统相互作用的抗凝剂。活化 PC 具有广泛的抗炎作用，其介导机制是通过调节白细胞功能和提供血管屏障保护。我们研究了活化 PC 对实验性自身免疫性脑脊髓炎（EAE），即多发性硬化症动物模型发病机制的影响。我们通过全身给予抗 PC/活化 PC（抗 PC）单克隆抗体来调节 EAE 诱导期间循环中的活化 PC 水平。我们最初假设抑制活化 PC 可能导致炎症环境加剧，从而导致 EAE 发病机制增加。与这一假设相反，用抗 PC 抗体治疗的小鼠（抗 PC 小鼠）表现出 EAE 减轻。有趣的是，尽管中枢神经系统的疾病严重程度和致病性条件轻微，但抗 PC 小鼠的大脑中有相当数量的白细胞浸润，与严重 EAE 的对照小鼠相当。此外，抗 PC 小鼠外周血中的 CD4(+) T 细胞减少，而各种 CD11b(+) 群体增加，特别是髓系来源的抑制细胞（MDSCs），一种以有效抑制 T 细胞增殖为特征的 CD11b(+)亚群。抗 PC 小鼠的 MDSC 表达增加了 T 细胞抑制因子，并有效地抑制了 T 细胞增殖。总体而言，我们的研究结果表明，活化 PC 抑制在多个方面影响 EAE 发病机制，特别是增加血管屏障通透性，这可通过大脑中有大量白细胞浸润来证明。此外，抑制活化 PC 调节了 CD11b(+)细胞的功能反应，导致 MDSC 的扩增和激活增加，而 MDSC 对 EAE 进展所需的 CD4(+) T 细胞具有抑制作用，从而导致 EAE 减轻。
