Mitochondria Regulate Neutrophil Activation by Generating ATP for Autocrine Purinergic Signaling

Bao, Yi; Ledderose, Carola; Seier, Thomas; Graf, Amelie F.; Brix, Bianca; Chong, Eritza; Junger, Wolfgang G.

doi:10.1074/jbc.m114.572495

Cited by 114 publications

(132 citation statements)

References 42 publications

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“…Recently, other evidence has emerged in support of a similar role for mitochondria in tumorigenesis [35][36][37]. We previously reported that mitochondria are central components of the purinergic signaling mechanisms that regulate immune cell functions [13,17,38,39]. Our current results show that highly active mitochondria in Jurkat cells upregulate the purinergic signaling processes that regulate cell metabolism and promote the proliferation of Jurkat cells.…”

Section: Discussionsupporting

confidence: 63%

Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling?

Ledderose

Woehrle

Ledderose

et al. 2016

Purinergic Signalling

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T cells respond to antigen stimulation with the rapid release of cellular ATP, which stimulates an autocrine feedback mechanism that regulates calcium influx through P2X receptors. This autocrine purinergic feedback mechanism plays an essential role in the activation of T cells resulting in cell proliferation and clonal expansion. We recently reported that increases in mitochondrial ATP production drive this stimulation-induced purinergic signaling mechanism but that low-level mitochondrial ATP production fuels basal T cell functions required to maintain vigilance of unstimulated T cells. Here we studied whether defects in these purinergic signaling mechanisms are involved in the unwanted proliferation of leukemia T cells. We found that acute leukemia T cells (Jurkat) possess a larger number and more active mitochondria than their healthy counterparts. Jurkat cells have higher intracellular ATP concentrations and generat more extracellular ATP than unstimulated T cells from healthy donors. As a result, increased purinergic signaling through P2X1 and P2X7 receptors elevates baseline levels of cytosolic Ca 2+ in Jurkat cells. We found that pharmacological inhibition of this basal purinergic signaling mechanism decreases mitochondrial activity, Ca 2+ signaling, and cell proliferation. Similar results were seen in the leukemic cell lines THP-1, U-937, and HL-60. Combined treatment with inhibitors of P2X1 or P2X7 receptors and the chemotherapeutic agent 6-mercaptopurine completely blocked Jurkat cell proliferation. Our results demonstrate that increased mitochondrial metabolism promotes autocrine purinergic signaling and uncontrolled proliferation of leukemia cells. These findings suggest that deranged purinergic signaling can result in T cell malignancy and that therapeutic targeting aimed at purinergic signaling is a potential strategy to combat T cell leukemia.

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Section: Discussionsupporting

confidence: 63%

Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling?

Ledderose

Woehrle

Ledderose

et al. 2016

Purinergic Signalling

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“…Activation of the P2X1 receptor requires extracellular ATP. Unlike well-established mechanisms of platelets releasing ATP through degranulation of dense granule constituents, activated neutrophils release ATP primarily through membrane Cx43 hemichannels and gap junction protein pannexin 1 (Panx1) channels, as described in previous reports (14,15). The present study demonstrated that LPS promoted neutrophils releasing ATP through the Cx43 hemichannels because the Cx43 inhibitor but not the Panx1 inhibitor decreased ATP release ( Fig.…”

Section: Atp Is Released From Lps-stimulated Neutrophils Via Cx43 Hemsupporting

confidence: 51%

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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“…specifically, there are multiple ATP release pathways in neutrophils, including the secretion of granules that store ATP, as the amount of ATP released is dependent on the concentration of the chemoattractant (13). These studies suggest the existence of granule-mediated ATP exocytosis.…”

mentioning

confidence: 83%

Vesicular nucleotide transporter mediates ATP release and migration in neutrophils

Harada

Kato

Miyaji

et al. 2018

Journal of Biological Chemistry

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Mitochondria Regulate Neutrophil Activation by Generating ATP for Autocrine Purinergic Signaling

Cited by 114 publications

References 42 publications

Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling?

Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling?

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

Vesicular nucleotide transporter mediates ATP release and migration in neutrophils

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