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Extracellular ADP facilitates monocyte recruitment in bacterial infection via ERK signaling.

Abstract
As the most prominent clinical drug targets for the inhibition of platelet aggregation, P2Y12 and P2Y13 have been found to be highly expressed in both platelets and macrophages. However, the roles and function of P2Y12/13 in the regulation of macrophage-mediated innate immune responses remain unclear. Here, we demonstrate that adenosine 5'-diphosphate (ADP), the endogenous ligand of P2Y1, P2Y12 and P2Y13, was released both in E. coli-infected mice and from macrophages treated with either lipopolysaccharide (LPS) or Pam3CSK4. Furthermore, the expression of P2Y13 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, P2Y1 is dispensable for ADP-mediated protection against bacterial infection. However, either P2Y12/P2Y13 deficiency or blocking the downstream signaling of P2Y12/P2Y13 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.
AuthorsXiaoyu Zhang, Juliang Qin, Junyan Zou, Zhangsheng Lv, Binghe Tan, Jueping Shi, Yihan Zhao, Hua Ren, Mingyao Liu, Min Qian, Bing Du
JournalCellular & molecular immunology (Cell Mol Immunol) Vol. 15 Issue 1 Pg. 58-73 (01 2018) ISSN: 2042-0226 [Electronic] China
PMID27867196 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Receptors, Purinergic P2
  • Adenosine Diphosphate
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Extracellular Signal-Regulated MAP Kinases
Topics
  • Adenosine Diphosphate (pharmacology)
  • Animals
  • Bacterial Infections (enzymology, immunology)
  • Cell Movement (drug effects)
  • Chemokine CCL2 (metabolism)
  • Cyclic AMP (metabolism)
  • Cyclic AMP-Dependent Protein Kinases (metabolism)
  • Escherichia coli (drug effects, physiology)
  • Extracellular Signal-Regulated MAP Kinases (metabolism)
  • Extracellular Space (chemistry)
  • Female
  • Host-Pathogen Interactions (drug effects)
  • MAP Kinase Signaling System (drug effects)
  • Macrophages (drug effects, metabolism)
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Monocytes (drug effects, metabolism)
  • Phosphorylation (drug effects)
  • RAW 264.7 Cells
  • Receptors, Purinergic P2 (metabolism)

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