P2Y 6 signaling selectively regulates TLR3-induced chemokine release in murine bone marrow-derived macrophages, with opposing effects on CCL2 and CXCL1
Year: 2026
Type: preprint
Abstract: 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 CXCL1 release. In agreement, the non-selective P2 receptor antagonists suramin and RB2 reduced poly(I:C)-induced CCL2 production. Among the highly expressed P2 receptors examined, selective inhibition of P2Y 6 with MRS2578 reproduced the effects of apyrase, decreasing CCL2 while increasing CXCL1 secretion. The absence of effects of MRS2578 in P2ry6 -deficient BMDMs confirmed the specificity of this antagonist. Transcriptional analysis further revealed that P2Y 6 inhibition reduced early poly(I:C)-induced Ccl2 and Cxcl10 expression while enhancing later Cxcl1 and Cxcl2 expression. In line with our previous works on other pattern-recognition receptors pathways and innate immune cells, this study further supports a role for extracellular nucleotides in shaping TLR-induced chemokine responses in macrophages.
Language: English
Subfield: Physiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7213453374