Tumor Necrosis Factor-α Blockade Corrects Monocyte/Macrophage Imbalance in Primary Immune Thrombocytopenia
Tumor Necrosis Factor-α Blockade Corrects Monocyte/Macrophage Imbalance in Primary Immune Thrombocytopenia
复制标题
肿瘤坏死因子-α 阻断可纠正原发性免疫性血小板减少症中的单核细胞/巨噬细胞失衡
DOI：
10.1055/s-0040-1722186
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发表时间：
2021-01-14
影响因子：
6.7
通讯作者：
Hou，Ming
中科院分区：
文献类型：
--
作者：
Zhao，Yajing;Xu，Pengcheng;Hou，Ming
原发性免疫性血小板减少症（ITP）是一种获得性自身免疫性出血性疾病。单核细胞和巨噬细胞是ITP中参与自身抗体介导的血小板清除的主要细胞。在本研究中，我们发现与健康对照组相比，ITP患者外周血促炎性CD 16+单核细胞的百分比增加，脾脏肿瘤坏死因子-α（TNF-α）表达巨噬细胞的频率升高。同时，我们观察到ITP患者血浆中TNF-α分泌升高以及总外周血单个核细胞和CD 14+单核细胞中TNF-α mRNA表达升高。值得注意的是，使用中和抗体进行的体外TNF-α阻断可通过抑制核因子κ B（NF-κB）信号传导途径显著降低向M1巨噬细胞的极化。此外，TNF-α阻断抑制巨噬细胞吞噬作用和T细胞刺激能力。最后，在ITP的被动和主动小鼠模型中，抗TNF-α治疗减少了非经典单核细胞和M1巨噬细胞的数量，改善了血小板在脾脏和肝脏中的滞留，并增加了ITP小鼠的血小板计数。总之，TNF-α阻断剂通过抑制NF-κB信号通路，降低了单核细胞和巨噬细胞促炎亚群的数量和功能，导致抗体介导的血小板破坏显著减弱。因此，TNF-α阻断可能是一种有前途的治疗策略，用于管理ITP。
Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. Monocytes and macrophages are the major cells involved in autoantibody-mediated platelet clearance in ITP. In the present study, we found increased percentages of peripheral blood proinflammatory CD16+monocytes and elevated frequencies of splenic tumor necrosis factor-α (TNF-α)-expressing macrophages in ITP patients compared with healthy controls. Concurrently, we observed elevated TNF-α secretion in plasma as well as higher TNF-α mRNA expression in total peripheral blood mononuclear cells and CD14+monocytes of ITP patients. Of note, in vitro TNF-α blockade with neutralizing antibody remarkably reduced polarization to M1 macrophages by inhibiting the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, TNF-α blockade dampened macrophage phagocytosis and T cell stimulatory capacity. Finally, in passive and active murine models of ITP, anti-TNF-α therapy reduced the number of nonclassical monocytes and M1 macrophages, ameliorated the retention of platelets in spleen and liver, and increased the platelet count of ITP mice. Taken together, TNF-α blockade decreased the number and function of proinflammatory subsets of monocytes and macrophages by inhibiting the NF-κB signaling pathway, leading to remarkable attenuation of antibody-mediated platelet destruction. Thus, TNF-α blockade may be a promising therapeutic strategy for the management of ITP.