Summary
A bioRxiv preprint reports that blocking the P2Y6 receptor reduced CCL2 but increased CXCL1 release from mouse macrophages stimulated through TLR3. The findings identify extracellular-nucleotide signaling as a selective regulator of inflammatory chemokine responses in this cell model.
A bioRxiv preprint reports that the P2Y6 receptor can push two chemokine responses in opposite directions when mouse macrophages are stimulated through Toll-like receptor 3 (TLR3). Blocking P2Y6 reduced secretion of CCL2 while increasing secretion of CXCL1, suggesting that extracellular-nucleotide signaling helps shape the composition of an innate immune response rather than simply amplifying or suppressing it as a whole.
The study was conducted in murine bone marrow-derived macrophages (BMDMs), a laboratory cell model. The researchers used poly(I:C), a synthetic molecule commonly used to stimulate TLR3, and measured the release of chemokines produced by the cells. The preprint was posted on bioRxiv on 16 September 2026 by researchers affiliated with Université Laval and the Centre de Recherche du CHU de Québec–Université Laval.
How the experiments separated the chemokine responses
Poly(I:C) stimulation induced both CCL2 and CXCL1 secretion from the BMDMs. CCL2 is broadly associated with the recruitment of monocytes and other immune cells, while CXCL1 is associated with neutrophil recruitment. Their opposing responses therefore represent a change in the type of inflammatory signal produced by the cells.
To test whether extracellular nucleotides were involved, the researchers used apyrase, an enzyme that degrades extracellular nucleotides. Apyrase reduced poly(I:C)-induced CCL2 release but enhanced CXCL1 release. Two non-selective P2 receptor antagonists, suramin and RB2, also reduced CCL2 production after TLR3 stimulation.
The researchers then focused on P2Y6, one of the highly expressed P2 receptors examined in the cells. Selective inhibition with MRS2578 reproduced the effects of apyrase: CCL2 secretion fell, while CXCL1 secretion increased. The inhibitor produced no such effects in macrophages from P2ry6-deficient mice, a genetic comparison that supported the specificity of the P2Y6-related response.
A timing-dependent effect on inflammatory signals
Transcriptional analysis showed that the effect was also visible at the level of gene activity. P2Y6 inhibition reduced early poly(I:C)-induced expression of Ccl2 and Cxcl10, while enhancing later expression of Cxcl1 and Cxcl2. This indicates that P2Y6 influences both which chemokines are produced and when their responses develop after TLR3 stimulation.
The result adds to evidence that extracellular nucleotides act as signalling molecules during innate immune activation. In this model, P2Y6 does not behave as a general on-off switch for inflammation. Its activity favours some TLR3-induced chemokine outputs while restraining others, potentially helping determine which immune cells are recruited during a response.
The evidence is currently limited to an in-vitro study of mouse bone marrow-derived macrophages and is presented as a bioRxiv preprint. The supplied abstract does not report the experiment's sample size, and the relevance of this P2Y6-dependent pattern to human macrophages, intact tissues or inflammatory disease remains to be tested.