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Concomitant activation of P2Y2 and P2Y6 receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Extracellular nucleotides regulate a variety of cellular responses involved in inflammation via the activation of P2 receptors. Here, we show that nucleotides regulate TLR2‐induced neutrophil migration both in vivo and in vitro. The nucleotide scavenger apyrase inhibited neutrophil recruitment in murine air pouches injected with the TLR2 agonist Pam3CSK4. In agreement, the supernatants of either human primary monocytes or monocytic cells (THP‐1 and U937) treated with Pam3CSK4 recruited significantly fewer neutrophils when the former cells were treated in the presence of apyrase. As demonstrated with inhibitory Ab, these supernatants induced neutrophil migration due to IL‐8 secretion. In addition, IL‐8 secretion was markedly diminished by the non‐selective P2 receptor antagonists reactive blue 2 and suramin, and by a selective P2Y6 antagonist, MRS2578. Selective antagonists of P2Y1 (MRS2500) and P2Y11 (NF157) did not affect IL‐8 release. The knockdown of either P2Y2 or P2Y6 with specific shRNA diminished IL‐8 secretion from Pam3CSK4‐treated THP‐1 cells. Altogether, these results show that extracellular nucleotides, via P2Y2 and P2Y6 receptors, regulate neutrophil migration by controlling TLR2‐induced IL‐8 release from human monocytes. In line with our previous work on TLR4, this study further supports the importance of nucleotides in bacterial‐induced neutrophil migration.