Antigen B from Echinococcus granulosus regulates macrophage phagocytosis by controlling TLR4 endocytosis in immune thrombocytopenia.

Yunfei Zhang, Yingbin Yue, Yongfeng Cheng, Hongjie Jiao, Mei Yan
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Abstract

Immune thrombocytopenia (ITP) is characterized by a reduction in platelet counts, stemming from an autoimmune-mediated process where platelets are excessively cleared by macrophages. This enhanced phagocytosis is a cardinal pathogenic mechanism in ITP. Antigen B (AgB), a principal component of the Echinococcus granulosus cyst fluid, plays a pivotal role in safeguarding the parasite from host immune defenses by modulating macrophage activation. In this study, we explored the potential of AgB to regulate macrophage activation in the context of ITP. Our observations indicated a diminished presence of M1 macrophages and a reduced phagocytic capacity in patients infected with E. granulosus sensu stricto. We isolated AgB from E. granulosus cyst fluid (EgCF) and discovered that it could suppress the polarization of M1 macrophages and weaken their phagocytic activity via Fcγ receptors, consequently alleviating thrombocytopenia in an ITP mouse model. At the molecular level, AgB was found to suppress the activation of nuclear factor kappa B (NF-κB) and interferon regulatory factor 3 (IRF3) by impeding their nuclear translocation, leading to a reduction in the generation of inflammatory cytokines. Furthermore, AgB was shown to inhibit Toll-like receptor 4 (TLR4) endocytosis and the recycling of CD14. In aggregate, our findings uncover a novel immunomodulatory mechanism of AgB, which suppresses macrophage phagocytosis by regulating TLR4 endocytosis and the subsequent activation of NF-κB and IRF3 signaling pathways. These insights shed new light on the molecular intricacies of E. granulosus-induced immune evasion and suggest that AgB may serve as a promising therapeutic agent for ITP.

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免疫性血小板减少症(ITP)的特点是血小板数量减少,其源于一种自身免疫介导的过程,即血小板被巨噬细胞过度清除。这种吞噬作用的增强是 ITP 的主要致病机制。抗原 B(AgB)是棘球蚴囊液的主要成分,它通过调节巨噬细胞的活化,在保护寄生虫免受宿主免疫防御的影响方面发挥着关键作用。在这项研究中,我们探讨了 AgB 在 ITP 中调节巨噬细胞活化的潜力。我们的观察结果表明,在感染了严格意义上的粒细胞埃希氏菌的患者中,M1 巨噬细胞的数量减少,吞噬能力下降。我们从肉芽肿埃希氏菌囊液(EgCF)中分离出了 AgB,并发现它能通过 Fcγ 受体抑制 M1 巨噬细胞的极化并削弱其吞噬活性,从而减轻了 ITP 小鼠模型中血小板减少的情况。在分子水平上,AgB 通过阻碍核因子卡巴 B(NF-κB)和干扰素调节因子 3(IRF3)的核转位,抑制了它们的活化,从而减少了炎症细胞因子的产生。此外,AgB 还能抑制 Toll 样受体 4(TLR4)的内吞和 CD14 的循环。总之,我们的研究结果揭示了 AgB 的一种新型免疫调节机制,它通过调节 TLR4 的内吞以及随后激活 NF-κB 和 IRF3 信号通路来抑制巨噬细胞的吞噬作用。这些发现揭示了肉芽肿埃希氏菌诱导的免疫逃避的分子奥秘,并表明AgB可作为一种治疗ITP的药物。
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