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P2Y(6) receptor inhibition perturbs CCL2-evoked signalling in human monocytic and peripheral blood mononuclear cells

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Hinnah Campwala, Darren W. Sexton, David C. Crossman, Samuel J. Fountain

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Abstract

The chemokine CCL2 serves to target circulating monocytes and other leukocytes to tissue during innate immune responses, and modulates the progression of chronic inflammatory disease through activation of the receptor CCR2. Here, we show that co-activation of the P2Y(6) purinergic receptor (encoded by P2RY6) occurs when THP-1 cells and human peripheral blood mononuclear cells sense CCL2 through CCR2. Furthermore, P2Y(6) receptor activation accounts for similar to 80% of the intracellular Ca2+ signal evoked by CCL2. Scavenging extracellular nucleotides with apyrase caused a fourfold reduction in THP-1 sensitivity to CCL2, whereas inhibition of CD39-like ectonucleotidases potentiated CCL2-evoked Ca2+ responses. Pharmacological inhibition of P2Y(6) impaired CCL2-evoked Ca2+ signalling and chemotaxis in peripheral blood mononuclear cells and THP-1 cells. Furthermore, stable P2Y(6) receptor knockdown (of twofold) in THP-1 cells impaired CCL2-evoked Ca2+ signalling, chemotaxis and adhesion to TNF alpha-treated HUVECs. We demonstrate that THP-1 cells rapidly secrete ATP during signalling downstream of the CCL2-CCR2 axis and suggest this might act as a mechanism for P2Y(6) receptor co-activation following CCL2 activation of the CCR2 receptor. The discovery that P2Y(6) receptor mediates leukocyte responsiveness to CCL2 represents a new mechanism by which to modulate CCL2 signals.

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Original languageEnglish
Pages (from-to)4964-4973
Number of pages10
JournalJournal of Cell Science
Volume127
Issue number22
Early online date30 Sep 2014
DOIs
Publication statusPublished - 15 Nov 2014

    Research areas

  • P2Y(6), Chemokine, Monocyte, Purinergic signalling

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