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

Abstract

<jats:p>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.</jats:p>

Control of Macrophage Inflammation by P2Y Purinergic Receptors

“…P2Y 2 receptor mRNA is expressed in human monocytes [ 22 , 23 ] and in monocyte-derived dendritic cells and macrophages [ 24 ]. In rodents, P2Y 2 receptor expression has been detected in murine [ 26 , 28 , 50 , 51 ] and rat [ 27 , 52 ] alveolar and peritoneal macrophages as well as in murine and rat brain-resident macrophages (microglia) [ 27 , 52 , 53 ]. In addition, the P2Y 2 receptor is expressed by osteoclasts [ 54 ].…”

“…ATP and UTP were shown to shape the pro-inflammatory response of macrophages via P2Y 2 receptor signaling. Application of UTP and ATP (100 µM) during a 3-h macrophage priming enhanced IL-1β production stimulated by LPS-induced NLRP3 inflammasome activation in murine peritoneal macrophages [ 51 ]. Pretreatment of macrophages with the P2Y 2 receptor inhibitor AR-C118925xx prevented the observed effects, and priming with nucleotides failed in macrophages isolated from mice lacking the P2Y 2 receptor.…”

Purinergic Signalling in Allogeneic Haematopoietic Stem Cell Transplantation and Graft-versus-Host Disease

“…ATP released during inflammation and cell damage can stimulate P2X7 on leukocytes to drive various inflammatory events such as DC migration [ 84 ], pro-inflammatory cytokine release from macrophages and DCs [ 85 ], and effector T cell activation [ 86 ]. Additionally, UTP can be released along with ATP to activate P2Y 2 to further promote leukocyte migration [ 87 , 88 ] and cytokine release [ 89 , 90 ]. ATP can be sequentially degraded by CD39 and CD73 to yield adenosine, thereby activating A 2A on leukocytes and resulting in the impairment of inflammatory events such as reduced pro-inflammatory cytokine release from T cells [ 91 , 92 ].…”

Quantitative Super-Resolution Imaging for the Analysis of GPCR Oligomerization

“…To demonstrate the potential of qPAINT to study GPCRs oligomerization status, we investigated the nanoscale distribution of the P2Y 2 receptor, a member of the d subgroup of the family A of GPCRs, in the cancer cell line AsPC-1, as it endogenously expresses high levels of this receptor and single cells are easily imaged due to its low levels of cell grouping [19]. P2Y 2 has been related to immune regulation, bone mineralisation, intraocular pressure, HIV-1 infection, and cancer metastasis and proliferation [22][23][24][25]. P2Y 2 has recently gained traction due to its role in several cancers such as breast, head and neck, prostate, and pancreatic [19,[25][26][27].…”