Anti-Inflammatory Therapy in Chronic Disease: Challenges and Opportunities

Positive Allosteric Modulation of SK Channels by Riluzole

P2X4 is a ligand-gated cation channel that is widely expressed amongst immune
cells, especially in monocytes and macrophages. Despite its expression profile, the
functional role of P2X4 in human macrophages has not been elucidated. This study
aimed to (i) investigate the contribution of P2X4 towards ATP-evoked Ca2+
responses and (ii) determine the role of P2X4 towards cytokine production in human
macrophages. Here, human THP-1-differentiated macrophages (TDM) and primary
monocyte-derived macrophages (MDMs) were utilized as human macrophage
models to investigate the contribution of P2X4 by means of Ca2+ measurements,
mRNA expression analysis and cytokine secretion assays. A side-by-side
comparison study of MDM generated through stimulation with either GM-CSF (GMMDM)
or M-CSF (M-MDM) illustrated that P2X4 has a bigger contribution towards
ATP-evoked Ca2+ responses in GM-MDM cells. In GM-MDM cells, P2Y11 and P2Y13
activation both contributed towards the amplitude and sustained phase of response,
while P2X4, but not P2X1 or P2X7, activation contributed towards the sustained
phase of ATP-evoked Ca2+ response. Employment of a cytokine and chemokine
mRNA profiler array in GM-MDM revealed that 100 μM ATP induced transforming
growth factor-b2 (TGF-b2) and C-X-C motif chemokine 5 (CXCL5). Selective
antagonism of P2X4 with PSB-12062 positively modulated ATP-mediated induction
of TGF-b2 gene expression while it inhibited ATP-mediated induction of CXCL5
gene expression. Although the effect on TGF-b2 was not translated at a protein
level, PSB-12062 inhibited ATP-mediated induction of CXCL5 protein synthesis and
secretion. Reciprocally, positive allosteric modulation of P2X4 with ivermectin
augmented ATP-mediated CXCL5 secretion. Inhibition of P2X7, P2Y11 or P2Y13 had
no effect on CXCL5 secretion. Altogether, we have identified a role for P2X4
activation in determining the duration of ATP-evoked intracellular Ca2+ response
and stimulating induction and secretion of CXCL5 in human primary macrophage.

P2X4 receptor in human macrophages: role in ATP-evoked calcium responses and cytokine production

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P2X4 receptor in human macrophages: role in ATP-evoked calcium responses and cytokine production