Signaling Through Purinergic Receptor P2Y2 Enhances Macrophage IL-1β Production.

Gonzalo De La Rosa,Ana I Gómez,María C Baños,Pablo Pelegrín

doi:10.3390/ijms21134686

Abstract

The release of nucleotides during necrosis or apoptosis has been described to have both proinflammatory and anti-inflammatory effect on the surrounding cells. Here we describe how low concentrations of UTP and ATP applied during macrophage priming enhance IL-1β production when subsequently the NLRP3 inflammasome is activated in murine resident peritoneal macrophages. Deficiency or pharmacological inhibition of the purinergic receptor P2Y2 reverted the increase of IL-1β release induced by nucleotides. IL-1β increase was found dependent on the expression of Il1b gene and probably involving JNK activity. On the contrary, nucleotides decreased the production of a different proinflammatory cytokines such as TNF-α. These results suggest that nucleotides could shape the response of macrophages to obtain a unique proinflammatory signature that might be relevant in unrevealing specific inflammatory conditions.

Highlights

The control of the maturation and release of the proinflammatory cytokine interleukin (IL)-1β and IL-18 in macrophages by the NLRP3 inflammasome complex is a tightly controlled two-step process
Murine residential peritoneal macrophages (RPMs) primed with a combination of LPS with ATP and UTP (NTPs) released higher amounts of IL-1β when NLRP3 inflammasome was activated compared to macrophages only primed with LPS (Figure 1A,B)
Macrophages are important immune cells to control the initiation of the inflammatory response due to the expression of a wide array of receptors [19], and are highly sensitive to stimulation with pathogen associated molecular patterns (PAMP) or DAMP moieties that will induce production of pro-IL-1β cytokine as well as activation of the NLRP3 inflammasome to generate the maturation of this cytokine [20]

Summary

Introduction

The control of the maturation and release of the proinflammatory cytokine interleukin (IL)-1β and IL-18 in macrophages by the NLRP3 inflammasome complex is a tightly controlled two-step process. We have recently found that activation of P2X7R before priming signal 1, leads to a mitochondrial damage and a later defect on NLRP3 activation [7], highlighting the different pathways associated to P2X7R signaling. Extracellular nucleotides such as ATP are indicative of cellular distress, released in small amounts during apoptosis or in faster, larger amounts during sudden cell death like necrosis or pyroptosis [3,8,9]. Extracellular nucleotides have been implicated in several inflammatory processes either promoting or reducing the inflammatory response depending on the context [10,11]

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Results

Conclusion