ATP‐induced cellular stress and mitochondrial toxicity in cells expressing purinergic P2X7 receptor

Seeland, Swen; Kettiger, Hélène; Murphy, Mark; Treiber, Alexander; Giller, Jasmin; Kiss, Andrea; Sube, Romain; Krähenbühl, Stephan; Hafner, Mathias; Huwyler, Jörg

doi:10.1002/prp2.123

Cited by 32 publications

(20 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While our study did not directly address this possibility, we did show that at least in part, inhibiting the inflammasome reduces ROS and that ROS is required to eliminate bacteria. Future studies will focus on delineating the mechanism of inflammasome-induced ROS production as there is some evidence suggesting that mitochondria, which can be affected by P2X activation, interact with the NLRP3 inflammasome [36, 37]. …”

Section: Discussionmentioning

confidence: 99%

Inflammasome Activation by ATP Enhances Citrobacter rodentium Clearance through ROS Generation

Bording-Jorgensen¹,

Alipour²,

Danesh³

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: Nod-like receptor family, pyrin domain containing 3 (NLRP3) is an important cytosolic sensor of cellular stress and infection. Once activated, NLRP3 forms a multiprotein complex (inflammasome) that triggers the maturation and secretion of interleukin (IL)-1β and IL-18. We aimed to define the consequences of NLRP3 induction, utilizing exogenous adenosine triphosphate (ATP) as an inflammasome activator, to determine if inflammasome activation increases macrophage killing of Citrobacter rodentium and define mechanisms. Methods: Bacterial survival was measured using a gentamicin protection assay. Inflammasome activation or inhibition in mouse J774A.1 macrophages were assessed by measuring IL-1β; cytokines and reactive oxygen species (ROS) were measured by ELISA and DCFDA, respectively. Results: Activation of the inflammasome increased bacterial killing by macrophages and its inhibition attenuated this effect with no impact on phagocytosis or cell death. Furthermore, inflammasome activation suppressed pro-inflammatory cytokines during infection, possibly due to more effective bacterial killing. While the infection increased ROS production, this effect was reduced by inflammasome inhibitors, indicating that ROS is inflammasome-dependent. ROS inhibitors increased bacterial survival in the presence of ATP, suggesting that inflammasome-induced bacterial killing is mediated, at least in part, by ROS activity. Conclusion: Improving inflammasome activity during infection may increase bacterial clearance by macrophages and reduce subsequent microbe-induced inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Inflammasome Activation by ATP Enhances Citrobacter rodentium Clearance through ROS Generation

Bording-Jorgensen¹,

Alipour²,

Danesh³

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…P2X7 activation and functions were investigated in details over the past decade and its roles in the danger signaling with respect to intracellular potassium efflux and NLRP3 inflammasome activation have considerably given an attention very recently [ 6 , 7 ]. Numerous studies have mentioned this receptor's functions in regulation of various molecular events and participation in inflammation associated diseases like arthritis and Alzheimer [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that ATP is a cytolytic stimulus and sustained activation of P2X7 by ATP leads to cell death in macrophages and microglia [ 6 , 9 , 43 – 47 ]. Nevertheless, the cytotoxicity induced by P2X7 is cell type dependent.…”

Section: Discussionmentioning

confidence: 99%

“…Thus extracellular ATP that can be confined locally at sites of damaged tissues is regarded as an endogenous damage associated molecular pattern (DAMP). Activation of P2X7 rapidly triggers Na + , K + and Ca 2+ ions across the plasma membrane, which is followed by increasing membrane permeability for larger organic cations and forming a large, non-selective pore allowing molecules with molecular weight up to 900 Da to enter the cells [ 5 , 6 ]. The large pore formation consequently initiates several cellular events, including activation of the NLRP3 inflammasome, opening of pannexin 1 and connexin hemichannels, membrane blebbing, ROS production, loss of mitochondrial membrane potential, and eventually cellular death [ 7 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Coordinate effects of P2X7 and extracellular acidification in microglial cells

et al. 2018

View full text Add to dashboard Cite

Extracellular adenosine 5′-triphosphate (ATP) is a damage-associated molecular pattern and contributes to inflammation associated diseases including cancer. Extracellular acidosis is a novel danger signal in the inflammatory sites, where it can modulate inflammation, immunity and tumor growth. Extracellular acidification was shown to inhibit P2X7-mediated channel currents, while it remains unknown how acidification and P2X7 together affect cellular responses. Here, we treated BV-2 microglial cells with ATP in a short period (<15 min) or a sustained acidified condition. For short acidification we compared the actions of neutralized ATP and acidic ATP in a condition with pH buffering. For sustained acidification, we treated cells with neutralized ATP in acidic medium or acidic ATP in medium without pH buffering. In the short acidified condition, neutralized ATP induced higher responses than acidic ATP to increase intracellular calcium and reactive oxygen species, decrease intracellular potassium and induce cell death. In contrast, these cellular responses and mitochondrial fission caused by neutralized ATP were enhanced by pH 6.0 and pH 4.5 media. P2X7 activation can also rapidly block mitochondrial ATP turnover and respiration capacity, both of which were mimicked by nigericin and enhanced by acidity. Taken together P2X7-mediated ionic fluxes and reactive oxygen species production are attenuated under short acidification, while sustained acidification itself can induce mitochondrial toxicity which deteriorates the mitochondrial function under P2X7 activation.

show abstract

“…This, would in turn, result in elevated serum extracellular ATP (eATP) released from cells undergoing apoptosis and through signaling pathways. eATP, at sufficiently high concentrations is a well-established signaling molecule that drives cascades of inflammation through cellular P2 receptors and is indicated in both acute and chronic/autoimmune inflammatory pathologies ( 89 ). Preliminary data from our own group show a significant increase in eATP at the onset of diabetes in NOD females relative to earlier time points in disease progression and to non-progressing NOD females.…”

Section: Folic Acid Nk Viral Response and T1d: Tying It All Togethementioning

confidence: 99%

The Folate Cycle As a Cause of Natural Killer Cell Dysfunction and Viral Etiology in Type 1 Diabetes

Bayer

Fraker

2017

Front. Endocrinol.

View full text Add to dashboard Cite

The folate pathway is critical to proper cellular function and metabolism. It is responsible for multiple functions, including energy (ATP) production, methylation reactions for DNA and protein synthesis and the production of immunomodulatory molecules, inosine and adenosine. These play an important role in immune signaling and cytotoxicity. Herein, we hypothesize that defects in the folate pathway in genetically susceptible individuals could lead to immune dysfunction, permissive environments for chronic cyclical latent/lytic viral infection, and, ultimately, the development of unchecked autoimmune responses to infected tissue, in this case islet beta cells. In the context of type 1 diabetes (T1D), there has been a recent increase in newly diagnosed cases of T1D in the past 20 years that has exceeded previous epidemiological predictions with yet unidentified factor(s). This speaks to a potential environmental trigger that adversely affects immune responses. Most research into the immune dysfunction of T1D has focused on downstream adaptive responses of T and B cells neglecting the role of the upstream innate players such as natural killer (NK) cells. Constantly, surveilling the blood and tissues for pathogens, NK cells remove threats through direct cytotoxic responses and recruitment of adaptive responses using cytokines, such as IL-1β and IFN-γ. One long-standing hypothesis suggests viral infection as a potential trigger for the autoimmune response in T1D. Recent data suggest multiple viruses as potential causal agents. Intertwined with this is an observed reduced NK cell enumeration, cytotoxicity, and cytokine signaling in T1D patients. Many of the viruses implicated in T1D are chronic latent/lysogenic infections with demonstrated capacity to reduce NK cell response and number through mechanisms that resemble those of pregnancy tolerance. Defects in the folate pathway in T1D patients could result in decreased immune response to viral infection or viral reactivation. Dampened NK responses to infections result in improper signaling, improper antigen presentation, and amplified CD8+ lymphocyte proliferation and cytotoxicity, a hallmark of beta cell infiltrates in patients with T1D onset. This would suggest a critical role for NK cells in T1D development linked to viral infection and the importance of the folate pathway in maintaining proper NK response.

show abstract

ATP‐induced cellular stress and mitochondrial toxicity in cells expressing purinergic P2X7 receptor

Cited by 32 publications

References 53 publications

Inflammasome Activation by ATP Enhances Citrobacter rodentium Clearance through ROS Generation

Inflammasome Activation by ATP Enhances Citrobacter rodentium Clearance through ROS Generation

Coordinate effects of P2X7 and extracellular acidification in microglial cells

The Folate Cycle As a Cause of Natural Killer Cell Dysfunction and Viral Etiology in Type 1 Diabetes

Contact Info

Product

Resources

About