Extracellular ADP facilitates monocyte recruitment in bacterial infection via ERK signaling
Extracellular ADP facilitates monocyte recruitment in bacterial infection via ERK signaling
复制标题
细胞外 ADP 通过 ERK 信号传导促进细菌感染中单核细胞的募集
DOI：
10.1038/cmi.2016.56
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发表时间：
2018-01-01
影响因子：
24.1
通讯作者：
Du, Bing
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoyu;Qin, Juliang;Du, Bing
As the most prominent clinical drug targets for the inhibition of platelet aggregation, P2Y 12 and P2Y 13 have been found to be highly expressed in both platelets and macrophages. However, the roles and function of P2Y 12/13 in the regulation of macrophage-mediated innate immune responses remain unclear. Here, we demonstrate that adenosine 5′-diphosphate (ADP), the endogenous ligand of P2Y 1, P2Y 12 and P2Y 13, was released both in E. coli-infected mice and from macrophages treated with either lipopolysaccharide (LPS) or Pam3CSK4. Furthermore, the expression of P2Y 13 was clearly increased in both LPS-treated macrophages and tuberculosis patients. ADP protected mice from E. coli 0111-induced peritonitis by recruiting more macrophages to the infected sites. Consistent with this, ADP and ADP-treated cell culture medium attracted more macrophages in the transwell assay by enhancing the expression of MCP-1. Nevertheless, P2Y 1 is dispensable for ADP-mediated protection against bacterial infection. However, either P2Y 12/P2Y 13 deficiency or blocking the downstream signaling of P2Y 12/P2Y 13 blocked the ADP-mediated immune response and allowed more bacteria to persist in the infected mice. Furthermore, extracellular signal-regulated kinase (ERK) phosphorylation was clearly increased by ADP, and this type of activation could be blocked by either forskolin or analogs of cyclic AMP (cAMP)(for example, 8-bromo-cAMP). Accordingly, ADP-induced MCP-1 production and protection against bacterial infection could also be reduced by U0126, forskolin and 8-bromo-cAMP. Overall, our study reveals a relationship between danger signals and innate immune responses, which suggests the potential therapeutic significance of ADP-mediated purinergic signaling in infectious diseases.
