Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway.
Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway.
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DOI：
10.1038/srep15859
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发表时间：
2015-11-03
影响因子：
4.6
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Zhang S;Yu M;Guo Q;Li R;Li G;Tan S;Li X;Wei Y;Wu M
革兰氏阴性菌产生的脂多糖通过Toll样受体4(TLR4)激活宿主细胞的质膜信号，从而触发先天的炎症反应，但其机制仍未完全阐明。在这里，我们揭示了膜联蛋白A2(ANXA2)在宿主防御感染中的作用，因为ANXA2−/−小鼠对革兰氏阴性菌诱导的脓毒症高度敏感，炎症反应增强。计算分析和生化实验证实，结构性AnxA2的表达促进了TLR4的内化和随后的转位到早期内膜。它激活TRAM依赖的内体信号，导致抗炎细胞因子的释放。重要的是，AnxA2缺乏延长了TLR4介导的来自质膜的信号，这归因于促炎细胞因子(IL-6、肿瘤坏死因子α和IL-1β)的产生。因此，AnxA2通过TLR4启动的TRAM-TRIF途径直接对炎症反应起负性调节作用。这项研究揭示了AnxA2在感染引发的炎症中是一个关键的调节因子，它保护宿主免受过度的炎症损害。
Lipopolysaccharide (LPS) derived from Gram-negative bacteria activates plasma membrane signaling via Toll-like receptor 4 (TLR4) on host cells and triggers innate inflammatory responses, but the underlying mechanisms remain to be fully elucidated. Here we reveal a role for annexin A2 (AnxA2) in host defense against infection as anxa2−/− mice were highly susceptible to Gram-negative bacteria-induced sepsis with enhanced inflammatory responses. Computing analysis and biochemical experiments identified that constitutive AnxA2 expression facilitated TLR4 internalization and its subsequent translocation into early endosomal membranes. It activated the TRAM-dependent endosomal signaling, leading to the release of anti-inflammatory cytokines. Importantly, AnxA2 deficiency prolonged TLR4-mediated signaling from the plasma membrane, which was attributable to pro-inflammatory cytokine production (IL-6, TNFα and IL-1β). Thus, AnxA2 directly exerted negative regulation of inflammatory responses through TLR4-initiated TRAM-TRIF pathway occurring on endosomes. This study reveals AnxA2 as a critical regulator in infection-initiated inflammation, which protects the host from excessive inflammatory damage.