Purinergic Control of T Cell Activation by ATP Released Through Pannexin-1 Hemichannels

Schenk, Ursula; Westendorf, Astrid M.; Radælli, Enrico; Casati, Anna; Ferro, Micol; Fumagalli, Marta; Verderio, Claudia; Buer, Jan; Scanziani, Eugenio; Grassi, Fabio

doi:10.1126/scisignal.1160583

Cited by 371 publications

(461 citation statements)

References 76 publications

(114 reference statements)

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“…5C, 5D). In an intestinal inflammation model of immunocompromised Cd3e 2/2 mice transferred with conventional T cells, oATP treatment increased the number of Foxp3 + CD4 + T cells in MLNs of the diseased mice (14). However, Entpd7 2/2 mice treated with oATP did not show any increase in the number of Foxp3 + T cells in MLNs or the small intestinal lamina propria (Fig.…”

Section: Commensal Microbiota-dependent Atp-dependent Increase In Thmentioning

confidence: 90%

Ecto-Nucleoside Triphosphate Diphosphohydrolase 7 Controls Th17 Cell Responses through Regulation of Luminal ATP in the Small Intestine

Kusu

Kayama

Kinoshita

et al. 2013

The Journal of Immunology

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Extracellular ATP is released from live cells in controlled conditions, as well as dying cells in inflammatory conditions, and, thereby, regulates T cell responses, including Th17 cell induction. The level of extracellular ATP is closely regulated by ATP hydrolyzing enzymes, such as ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases). ENTPDase1/CD39, which is expressed in immune cells, was shown to regulate immune responses by downregulating the ATP level. In this study, we analyzed the immunomodulatory function of ENTPDase7, which is preferentially expressed in epithelial cells in the small intestine. The targeted deletion of Entpd7 encoding ENTPDase7 in mice resulted in increased ATP levels in the small intestinal lumen. The number of Th17 cells was selectively increased in the small intestinal lamina propria in Entpd7−/− mice. Th17 cells were decreased by oral administration of antibiotics or the ATP antagonist in Entpd7−/− mice, indicating that commensal microbiota-dependent ATP release mediates the enhanced Th17 cell development in the small intestinal lamina propria of Entpd7−/− mice. In accordance with the increased number of small intestinal Th17 cells, Entpd7−/− mice were resistant to oral infection with Citrobacter rodentium. Entpd7−/− mice suffered from severe experimental autoimmune encephalomyelitis, which was associated with increased numbers of CD4+ T cells producing both IL-17 and IFN-γ. Taken together, these findings demonstrate that ENTPDase7 controls the luminal ATP level and, thereby, regulates Th17 cell development in the small intestine.

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Section: Commensal Microbiota-dependent Atp-dependent Increase In Thmentioning

confidence: 90%

Ecto-Nucleoside Triphosphate Diphosphohydrolase 7 Controls Th17 Cell Responses through Regulation of Luminal ATP in the Small Intestine

Kusu

Kayama

Kinoshita

et al. 2013

The Journal of Immunology

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“…The usefulness of oATP (nonselective P2X receptors antagonist) was proposed for the treatment rheumatoid arthritis and multiple sclerosis after promising use in a mouse model of arthritic pain and EAE [118]. oATP was successfully applied to limit T cellmediated inflammation in mouse models of type 1 diabetes and inflammatory bowel disease [29,118]. oATP, suramine, and pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid significantly reduced allergic airway inflammatory response in the OVA-mediated model of asthma [91].…”

Section: Discussionmentioning

confidence: 99%

“…The connexinregulated ATP release has been shown for astrocytes [26], while pannexin channels are responsible for ATP secretion from an oocyte heterologous expression system [27], from erythrocytes in response to low oxygen or to sheer stress [28], and from activated T lymphocytes upon T cell receptor stimulation [29].…”

Section: Mast Cellsmentioning

confidence: 99%

P2 receptor-mediated signaling in mast cell biology

Bulanova

Bulfone–Paus∥

2009

Purinergic Signalling

100

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Mast cells are widely recognized as effector cells of allergic inflammatory reactions. They contribute to the pathogenesis of different chronic inflammatory diseases, wound healing, fibrosis, thrombosis/fibrinolysis, and antitumor immune responses. In this paper, we summarized the role of P2X and P2Y receptors in mast cell activation and effector functions. Mast cells are an abundant source of ATP which is stored in their granules and secreted upon activation. We discuss the contribution of mast cells to the extracellular ATP release and to the maintenance of extracellular nucleotides pool. Recent publications highlight the importance of purinergic signaling for the pathogenesis of chronic airway inflammation. Therefore, the role of ATP and P2 receptors in allergic inflammation with focus on mast cells was analyzed. Finally, ATP functions as mast cell autocrine/paracrine factor and as messenger in intercellular communication between mast cells, nerves, and glia in the central nervous system.

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“…For example, the mustard oil receptor TRPA1 responds to allyl-isothiocyanate to mediate YO-PRO-1 transport (35,36). Moreover, anionic transmitters ATP or GABA can pass pores of pannexin or bestrophin, respectively, underlying nonvesicular release of autocrine or paracrine factors in synapses (37)(38)(39)(40)(41). Analogously, the remarkable permeability of the TRPV1 pore presents a novel route for delivery of membrane impermeable local anesthetics selectively into pain sensing neurons (14).…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent targeting of TRPV1 with a pore-permeating capsaicin analog

Wang

Chuang³

et al. 2011

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

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The capsaicin receptor TRPV1 is the principal transduction channel for nociception. Excessive TRPV1 activation causes pathological pain. Ideal pain mangement requires selective inhibition of hyperactive pain-sensing neurons, but sparing normal nociception. We sought to determine whether it is possible to use activity-dependent TRPV1 agonists to identify nerves with excessive TRPV1 activity, as well as exploit the TRPV1 pore to deliver charged anesthetics for neuronal silencing. We synthesized a series of permanently charged capsaicinoids and found that one, cap-ET, efficaciously evoked TRPV1-dependent entry of Ca 2+ or the large cationic dye YO-PRO-1 comparably to capsaicin, but far smaller electrical currents. Cap-ETinduced YO-PRO-1 transport required permeation of both the agonist and the dye through the TRPV1 pore and could be enhanced by kinase activation or oxidative covalent modification. Moreover, cap-ET reduced capsaicin-induced currents by a voltage-dependent block of the pore. A low dose of cap-ET elicited entry of permanently charged Na + channel blockers to effectively suppress Na + currents in sensory neurons presensitized with oxidative chemicals. These results implicate therapeutic potential of these unique TRPV1 agonists exhibiting activity-dependent ion transport but of minimal pain-producing risks.activity-dependent capsaicinoids | hyperalgesia | ion permeation | selective analgesia C apsaicin, a small lipophilic molecule from hot chili peppers, acts on sensory neurons by opening the TRPV1 channel. TRPV1 is activated by noxious temperatures (>43°C) and serves as an integrator for major pain-producing signals (1, 2). Inflammatory hyperalgesia is dramatically reduced in mice lacking TRPV1 (3, 4). Besides being an attractive target for pain management, TRPV1 regulates autonomic function, such as body temperature, blood vessel tone, and release of transmitters from sensory nerves (5-9). TRPV1 activated by capsaicin at a concentration far below the pain-producing threshold triggers neuropeptide release (7) and production of other second messengers (10). In light of the complexity of TRPV1 actions in physiology, one major challenge in developing TRPV1-based pain treatment is to target therapeutic compounds to selectively inhibit hyperactive nociceptive neurons while sparing nerves of normal thresholds for pain detection.Capsaicin is among the most powerful chemical agonists of TRPV1. Being small and hydrophobic, capsaicin crosses the plasma membrane readily to reach its intracellular ligand-binding site on TRPV1 (11, 12), leading to channel activation and cation permeation. TRPV1 activation rapidly depolarizes nerves to evoke acute pain sensation and allows Ca 2+ entry to initiate downstream signaling events such as neuropeptide release or production of other second messengers. Nevertheless, TRPV1 activation facilitates cellular transport of organic cations such as tetraethylammonium (TEA), N-methylglucamine (NMG) (13), and the quaternary ammonium Na + channel blocker QX-314 (14) or even larger fluor...

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Purinergic Control of T Cell Activation by ATP Released Through Pannexin-1 Hemichannels

Abstract: Pannexin hemichannel–mediated release of ATP provides an autocrine, costimulatory signal for T cell activation.

Cited by 371 publications

References 76 publications

Ecto-Nucleoside Triphosphate Diphosphohydrolase 7 Controls Th17 Cell Responses through Regulation of Luminal ATP in the Small Intestine

Ecto-Nucleoside Triphosphate Diphosphohydrolase 7 Controls Th17 Cell Responses through Regulation of Luminal ATP in the Small Intestine

P2 receptor-mediated signaling in mast cell biology

Activity-dependent targeting of TRPV1 with a pore-permeating capsaicin analog

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