P2Y6 signaling selectively regulates TLR3-induced chemokine release in murine bone marrow-derived macrophages, with opposing effects on CCL2 and CXCL1
Extracellular nucleotides regulate diverse inflammatory responses through the activation of P2 receptors. Here, we show that nucleotides regulate TLR3-induced chemokine responses in murine bone marrow-derived macrophages (BMDMs). Stimulation with the TLR3 agonist, poly(I:C), induced CCL2 and CXCL1 secretion, whereas degradation of extracellular nucleotides with apyrase reduced CCL2 but enhanced…
P2Y6 signaling selectively regulates TLR3-induced chemokine release in murine bone marrow-derived macrophages, with opposing effects on CCL2 and CXCL1, according to a recent study. The researchers found that stimulation of TLR3 with the poly(I:C) agonist induced the secretion of both CCL2 and CXCL1. However, degradation of extracellular nucleotides using apyrase reduced CCL2 levels while enhancing CXCL1 release.
Non-selective P2 receptor antagonists suramin and RB2 were found to reduce poly(I:C)-induced CCL2 production. Among the highly expressed P2 receptors studied, selective inhibition of P2Y6 using MRS2578 replicated the effects of apyrase, resulting in decreased CCL2 and increased CXCL1 secretion. The absence of MRS2578 effects in P2ry6-deficient BMDMs confirmed the specificity of this antagonist.
Transcriptional analysis revealed that P2Y6 inhibition reduced early Ccl2 and Cxcl10 expression while enhancing later Cxcl1 and Cxcl2 expression. This study supports the role of extracellular nucleotides in shaping TLR-induced chemokine responses in macrophages.
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