Toll-Like Receptor-Mediated Activation of CD39 Internalization in BMDCs Leads to Extracellular ATP Accumulation and Facilitates P2X7 Receptor Activation
Toll-Like Receptor-Mediated Activation of CD39 Internalization in BMDCs Leads to Extracellular ATP Accumulation and Facilitates P2X7 Receptor Activation
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BMDC 中 Toll 样受体介导的 CD39 内化激活导致细胞外 ATP 积累并促进 P2X7 受体激活
DOI：
10.3389/fimmu.2019.02524
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发表时间：
2019-10-31
影响因子：
7.3
通讯作者：
Peng, Xiaoxiang
中科院分区：
文献类型：
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作者：
Zhao, Ronglan;Qiao, Jinjuan;Peng, Xiaoxiang
Toll样受体（TLR）通过识别内源性或微生物来源的保守分子配体来触发先天性免疫应答。尽管TLR的激活、功能和信号通路已经得到了很好的研究，但它们在特定细胞类型，特别是先天免疫细胞中的确切功能需要进一步阐明。在这项研究中，我们发现，当显着减少量的膜CD 39，三磷酸腺苷（ATP）降解酶，检测脂多糖（LPS）处理的骨髓来源的树突状细胞（BMDCs），CD 39 mRNA的表达，和全细胞CD 39的表达是在相同的水平，在未经处理的BMDCs。进一步的实验表明，LPS处理的BMDCs中膜CD 39表达的下调是由内吞作用介导的，导致膜暴露的CD 39下调，这与ATP代谢中的酶活性降低和细胞外ATP积累增加正相关。ATP通过激活P2 X7信号通路促进BMDCs细胞内钙的积累和IL-1 β的产生。进一步的研究表明，不仅LPS，而且其他TLR配体，不包括polyI：C，诱导BMDCs中的CD 39内化，并且MyD 88通路在此过程中是关键的。结果表明，TLR配体诱导的DC中CD 39内化的活化引起ATP积累增加，导致介导促炎作用的P2 X7受体活化。考虑到细胞外ATP积累对免疫反应和炎症的强烈调节作用，对DC上膜CD 39表达的操纵可能对炎症反应的调节和治疗具有意义。
Toll-like receptors (TLRs) trigger innate immune responses through their recognition of conserved molecular ligands of either endogenous or microbial origin. Although activation, function, and signaling pathways of TLRs were already well-studied, their precise function in specific cell types, especially innate immune cells, needs to be further clarified. In this study, we showed that when significantly decreased amounts of membrane CD39, an adenosine triphosphate (ATP)-degrading enzyme, were detected in lipopolysaccharide (LPS)-treated bone marrow-derived dendritic cells (BMDCs), Cd39 mRNA expression, and whole-cell CD39 expression were at the same levels as those in untreated BMDCs. Further experiments demonstrated that the downregulation of membrane CD39 expression in LPS-treated BMDCs was mediated by endocytosis, leading to membrane-exposed CD39 downregulation, which was positively associated with decreased enzymatic activity in ATP metabolism and increased extracellular ATP accumulation. The accumulated ATP promoted intracellular calcium accumulation and IL-1 beta production in BMDCs through P2X7 signaling activation. Further research revealed that not only LPS but also other TLR ligands, excluding polyI:C, induced CD39 internalization in BMDCs and that the MyD88 pathway was critical in this process. The results suggested that the activation of CD39 internalization in DCs induced by a TLR ligand caused increased ATP accumulation, leading to P2X7 receptor activation that mediated a proinflammatory effect. Considering the strong modulatory effect of extracellular ATP accumulation on the immune response and inflammation, the manipulation of membrane CD39 expression on DCs may have implications on the regulation and treatment of inflammatory responses.