Control of Macrophage Inflammation by P2Y Purinergic Receptors

Klaver, Dominik; Thurnher, Martin

doi:10.3390/cells10051098

Cited by 36 publications

(25 citation statements)

References 156 publications

(274 reference statements)

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“…iScience 24, 103478, December 17, 2021 iScience Article ATP and its metabolites have become a critical component of multiple diseases, including HIV and COVID-19 (Abouelkhair, 2020;Alves et al, 2020;de Oliveira et al, 2021;Dos Anjos et al, 2020;Edwards, 2021;Fonteles et al, 2020;Franciosi et al, 2021;Klaver and Thurnher, 2021;Mishra et al, 2021;Pacheco and Faria, 2021;Shan et al, 2020;Simoes and Bagatini, 2021). Our data in long-term HIV-infected individuals indicate that several chronic effects of HIV are correlated with ATP dysfunction and vascular disease, such as cognitive impairment (Velasquez et al, 2020).…”

Section: Ll Open Accessmentioning

confidence: 72%

Pannexin-1 channel opening is critical for COVID-19 pathogenesis

Luu¹,

Valdebenito²,

Scemes³

et al. 2021

iScience

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly rampaged worldwide, causing a pandemic of coronavirus disease (COVID -19), but the biology of SARS-CoV-2 remains under investigation. We demonstrate that both SARS-CoV-2 spike protein and human coronavirus 229E (hCoV-229E) or its purified S protein, one of the main viruses responsible for the common cold, induce the transient opening of Pannexin-1 (Panx-1) channels in human lung epithelial cells. However, the Panx-1 channel opening induced by SARS-CoV-2 is greater and more prolonged than hCoV-229E/S protein, resulting in an enhanced ATP, PGE 2 , and IL-1b release. Analysis of lung lavages and tissues indicate that Panx-1 mRNA expression is associated with increased ATP, PGE 2 , and IL-1b levels. Panx-1 channel opening induced by SARS-CoV-2 spike protein is angiotensin-converting enzyme 2 (ACE-2), endocytosis, and furin dependent. Overall, we demonstrated that Panx-1 channel is a critical contributor to SARS-CoV-2 infection and should be considered as an alternative therapy.

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Section: Ll Open Accessmentioning

confidence: 72%

Pannexin-1 channel opening is critical for COVID-19 pathogenesis

Luu¹,

Valdebenito²,

Scemes³

et al. 2021

iScience

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“…The inflammatory functions of HMGB1 are mediated through the receptor for advanced glycation end products (RAGE), TLR2, TLR4, and TLR9 [44,45]. ATP activates P2 purinergic receptors, through which it is involved in multiple pulmonary disorders [46,47], while dsDNA including mitochondrial DNA triggers an innate immune response through DNA sensors [48,49]. On the basis of these results, we posit that enhanced necroptosis in IFNγ-activated lung epithelial cells not only promotes cell death but also accelerates the release of immune-stimulatory DAMPs, through which they may contribute to the exaggerated tissue injury, inflammation and lung dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Qin

Shetty

Tucker

et al. 2022

Cells

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Necroptosis, a form of programmed lytic cell death, has emerged as a driving factor in the pathogenesis of acute lung injury (ALI). As ALI is often associated with a cytokine storm, we determined whether pro-inflammatory cytokines modulate the susceptibility of lung cells to necroptosis and which mediators dominate to control necroptosis. In this study, we pretreated/primed mouse primary lung epithelial and endothelial cells with various inflammatory mediators and assessed cell type-dependent responses to different necroptosis inducers and their underlying mechanisms. We found that interferon-γ (IFNγ) as low as 1 ng/mL preferentially promoted necroptosis and accelerated the release of damage-associated molecular patterns from primary alveolar and airway epithelial cells but not lung microvascular endothelial cells. Type-I IFNα was about fifty-fold less effective than IFNγ. Conversely, TNFα or agonists of Toll-like receptor-3 (TLR3), TLR4, TLR7 and TLR9 had a minor effect. The enhanced necroptosis in IFNγ-activated lung epithelial cells was dependent on IFNγ signaling and receptor-interacting protein kinase-3. We further showed that necroptosis effector mixed lineage kinase domain-like protein (MLKL) was predominantly induced by IFNγ, contributing to the enhanced necroptosis in lung epithelial cells. Collectively, our findings indicate that IFNγ is a potent enhancer of lung epithelial cell susceptibility to necroptosis.

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“…In response to TLR ligands (e.g., lipopolysaccharide [LPS], a constituent of the cell membrane of gram negative bacteria) and the cytokine interferon-γ (IFN-γ), macrophages undergo activation to a pro-inflammatory, classic type termed M1 [ 25 , 26 ]. M1 macrophages are amoeboid in shape, are able to phagocytose pathogenic bacteria, and typically release destructive inflammatory mediators such as pro-inflammatory cytokines (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α]), chemokines, proteases, reactive oxygen/nitrogen species, and probably also the excitotoxic ATP and glutamate by vesicular exocytosis [ 27 , 28 ]. Macrophages may also undergo M2 activation, which clear cellular debris through phagocytosis and release numerous protective factors (IL-4, IL-13, nerve growth factor [NGF], fibroblast growth factor [FGF]) [ 25 , 26 ].…”

Section: The P2x7r At Macrophagesmentioning

confidence: 99%

Inherent P2X7 Receptors Regulate Macrophage Functions during Inflammatory Diseases

Ren

Rubini

Tang

et al. 2021

IJMS

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Macrophages are mononuclear phagocytes which derive either from blood-borne monocytes or reside as resident macrophages in peripheral (Kupffer cells of the liver, marginal zone macrophages of the spleen, alveolar macrophages of the lung) and central tissue (microglia). They occur as M1 (pro-inflammatory; classic) or M2 (anti-inflammatory; alternatively activated) phenotypes. Macrophages possess P2X7 receptors (Rs) which respond to high concentrations of extracellular ATP under pathological conditions by allowing the non-selective fluxes of cations (Na+, Ca2+, K+). Activation of P2X7Rs by still higher concentrations of ATP, especially after repetitive agonist application, leads to the opening of membrane pores permeable to ~900 Da molecules. For this effect an interaction of the P2X7R with a range of other membrane channels (e.g., P2X4R, transient receptor potential A1 [TRPA1], pannexin-1 hemichannel, ANO6 chloride channel) is required. Macrophage-localized P2X7Rs have to be co-activated with the lipopolysaccharide-sensitive toll-like receptor 4 (TLR4) in order to induce the formation of the inflammasome 3 (NLRP3), which then activates the pro-interleukin-1β (pro-IL-1β)-degrading caspase-1 to lead to IL-1β release. Moreover, inflammatory diseases (e.g., rheumatoid arthritis, Crohn’s disease, sepsis, etc.) are generated downstream of the P2X7R-induced upregulation of intracellular second messengers (e.g., phospholipase A2, p38 mitogen-activated kinase, and rho G proteins). In conclusion, P2X7Rs at macrophages appear to be important targets to preserve immune homeostasis with possible therapeutic consequences.

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Control of Macrophage Inflammation by P2Y Purinergic Receptors

Cited by 36 publications

References 156 publications

Pannexin-1 channel opening is critical for COVID-19 pathogenesis

Pannexin-1 channel opening is critical for COVID-19 pathogenesis

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Inherent P2X7 Receptors Regulate Macrophage Functions during Inflammatory Diseases

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