Purinergic P2Y2 Receptors Promote Neutrophil Infiltration and Hepatocyte Death in Mice With Acute Liver Injury

Ayata, Cemil Korcan; Ganal, Stephanie; Hockenjos, Birgit; Willim, Karolina; Vieira, Rodolfo Paula; Grimm, Melanie; Robaye, Bernard; Boeynaems, Jean‐Marie; Virgilio, Francesco Di; Pellegatti, Patrizia; Diefenbach, Andreas; Idzko, Marco; Hasselblatt, Peter

doi:10.1053/j.gastro.2012.08.049

Cited by 77 publications

(64 citation statements)

References 42 publications

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“…In line with previous studies [4,5], we have shown that P2Y2 receptor deficiency results in decreased inflammation upon acute challenge with lipopolysaccharide. Specifically, our study demonstrates a role for P2Y2 receptors on myeloid cells.…”

Section: Discussionsupporting

confidence: 93%

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Myeloid P2Y2 receptor promotes acute inflammation but is dispensable for chronic high-fat diet-induced metabolic dysfunction

Adamson

Montgomery

Seaman

et al. 2017

Purinergic Signalling

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The purinergic receptor P2Y2 binds ATP to control chemotaxis of myeloid cells, and global P2Y2 receptor knockout mice are protected in models of acute inflammation. Chronic inflammation mediated by macrophages and other immune cells in adipose tissue contributes to the development of insulin resistance. Here, we investigate whether mice lacking P2Y2 receptors on myeloid cells are protected against acute and chronic inflammation. Wild-type mice were transplanted with either wild-type or P2Y2 receptor null bone marrow and treated with a sublethal dose of endotoxin as a model of acute inflammation, or fed a high-fat diet to induce obesity and insulin resistance as a model of chronic inflammation. P2Y2−/− chimeric mice were protected against acute inflammation. However, high-fat diet feeding induced comparable inflammation and insulin resistance in both WT and P2Y2 −/− chimeric mice. Of note, confocal microscopy revealed significantly fewer crown-like structures, assemblies of macrophages around adipocytes, in P2Y2 −/− chimeric mice compared to WT chimeric mice. We conclude that P2Y2 receptors on myeloid cells are important in mediating acute inflammation but are dispensable for the development of whole body insulin resistance in diet-induced obese mice.

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Section: Discussionsupporting

confidence: 93%

“…P2Y2 receptor null mice are protected in models of acute inflammation due to decreased leukocyte recruitment [4,5]. In macrophages, purinergic signaling controls chemotactic, phagocytic, and inflammatory responses [6].…”

Section: Introductionmentioning

confidence: 99%

Myeloid P2Y2 receptor promotes acute inflammation but is dispensable for chronic high-fat diet-induced metabolic dysfunction

Adamson

Montgomery

Seaman

et al. 2017

Purinergic Signalling

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“…Elevated circulating nucleotide levels and sustained purinergic signaling may consequently promote inflammatory diseases [7,8]. Consistent with this view, knockout of P2Y and ion channel purinergic receptors (P2X) in mice has been shown to significantly reduce inflammatory disease in the heart, liver, kidney, and other tissues [9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 85%

P2X receptors regulate adenosine diphosphate release from hepatic cells

Chatterjee

Sparks

2014

Purinergic Signalling

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Extracellular nucleotides act as paracrine regulators of cellular signaling and metabolic pathways. Adenosine polyphosphate (adenosine triphosphate (ATP) and adenosine diphosphate (ADP)) release and metabolism by human hepatic carcinoma cells was therefore evaluated. Hepatic cells maintain static nanomolar concentrations of extracellular ATP and ADP levels until stress or nutrient deprivation stimulates a rapid burst of nucleotide release. Reducing the levels of media serum or glucose has no effect on ATP levels, but stimulates ADP release by up to 10-fold. Extracellular ADP is then metabolized or degraded and media ADP levels fall to basal levels within 2-4 h. Nucleotide release from hepatic cells is stimulated by the Ca 2+ ionophore, ionomycin, and by the P2 receptor agonist, 2′3′-O-(4-benzoyl-benzoyl)-adenosine 5′-triphosphate (BzATP). Ionomycin (10 μM) has a minimal effect on ATP release, but doubles media ADP levels at 5 min. In contrast, BzATP (10-100 μM) increases both ATP and ADP levels by over 100-fold at 5 min. Ion channel purinergic receptor P2X7 and P2X4 gene silencing with small interference RNA (siRNA) and treatment with the P2X inhibitor, A438079 (100 μM), decrease ADP release from hepatic cells, but have no effect on ATP. P2X inhibitors and siRNA have no effect on BzATP-stimulated nucleotide release. ADP release from human hepatic carcinoma cells is therefore regulated by P2X receptors and intracellular Ca 2+ levels. Extracellular ADP levels increase as a consequence of a cellular stress response resulting from serum or glucose deprivation.

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“…ATP released from the leading edge of the neutrophil surface amplifies chemotactic signals and directs cell orientation by feedback through the P2Y2 receptor (4). Knockout of the P2Y2 receptor decreases liver infiltration by neutrophils and subsequent liver damage in mice with acute liver injury (5). The P2X1 receptor is also critical for neutrophil sensing of extracellular ATP, but its role in neutrophil migration during inflammation has not been thoroughly characterized.…”

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confidence: 99%

Endotoxin-induced autocrine ATP signaling inhibits neutrophil chemotaxis through enhancing myosin light chain phosphorylation

Wang

Qin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Although the neutrophil recruitment cascade during inflammation has been well described, the molecular players that halt neutrophil chemotaxis remain unclear. In this study, we found that lipopolysaccharide (LPS) was a potent stop signal for chemotactic neutrophil migration. Treatment with an antagonist of the ATP receptor (P2X1) in primary human neutrophils or knockout of the P2X1 receptor in neutrophil-like differentiated HL-60 (dHL-60) cells recovered neutrophil chemotaxis. Further observations showed that LPS-induced ATP release through connexin 43 (Cx43) hemichannels was responsible for the activation of the P2X1 receptor and the subsequent calcium influx. Increased intracellular calcium stopped neutrophil chemotaxis by activating myosin light chain (MLC) through the myosin light chain kinase (MLCK)-dependent pathway. Taken together, these data identify a previously unknown function of LPS-induced autocrine ATP signaling in inhibiting neutrophil chemotaxis by enhancing MLC phosphorylation, which provides important evidence that stoppage of neutrophil chemotaxis at infectious foci plays a key role in the defense against invading pathogens.endotoxin | neutrophil | chemotaxis | ATP | myosin light chain N eutrophils are the most abundant leukocytes in humans and the first blood cells to arrive at infectious sites as part of the innate cellular immune response. Following transmigration out of the blood vessel, neutrophils migrate through interstitial tissue toward the foci of damage. Then, neutrophil recruitment mobilizes near the pathogenic sites to eliminate pathogens and necrotic tissue. Although the neutrophil recruitment cascade during inflammation has been well described, the molecules that stop neutrophil chemotaxis remain unclear.Studies in recent decades have confirmed that extracellular ATP, as a purinergic signaling molecule, participates in the pathogenesis of various inflammatory diseases such as transplantation rejection, autoimmune disease, and bacterial infection (1). As a result of ectoapyrases and ectoadenosine triphosphatases (ecto-ATPases), which hydrolyze ATP into adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine (ADO), the concentration of extracellular ATP is maintained at ∼10 nmol/L (2). However, the intracellular ATP concentration in mammalian cells is 5-8 mmol/L. Owing to the 10 6 -fold ATP gradient difference, cell necrosis or activation at inflammatory sites causes a dramatic ATP release (2). By activating the P2X (P2X1-7 subtypes) and P2Y (P2Y1, -2, -4, -6, and -11-14 subtypes) receptor families, extracellular ATP contributes to the regulation of a variety of inflammatory cell responses (3). Given the high concentration of ATP in inflammatory tissues, the effects of extracellular ATP/P2 receptors on neutrophil migration have attracted much attention. ATP released from the leading edge of the neutrophil surface amplifies chemotactic signals and directs cell orientation by feedback through the P2Y2 receptor (4). Knockout of the P2Y2 receptor decreases liver infi...

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Purinergic P2Y2 Receptors Promote Neutrophil Infiltration and Hepatocyte Death in Mice With Acute Liver Injury

Cited by 77 publications

References 42 publications

Myeloid P2Y2 receptor promotes acute inflammation but is dispensable for chronic high-fat diet-induced metabolic dysfunction

Myeloid P2Y2 receptor promotes acute inflammation but is dispensable for chronic high-fat diet-induced metabolic dysfunction

P2X receptors regulate adenosine diphosphate release from hepatic cells

Endotoxin-induced autocrine ATP signaling inhibits neutrophil chemotaxis through enhancing myosin light chain phosphorylation

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