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      Purine Release, Metabolism, and Signaling in the Inflammatory Response

      Author(s): 1 , 2 , 3 , 4
      Publication date Created:
      Publication date (Print):
      Journal: Annual Review of Immunology
      Publisher: Annual Reviews

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          Abstract

          ATP, NAD +, and nucleic acids are abundant purines that, in addition to having critical intracellular functions, have evolved extracellular roles as danger signals released in response to cell lysis, apoptosis, degranulation, or membrane pore formation. In general ATP and NAD +have excitatory and adenosine has anti-inflammatory effects on immune cells. This review focuses on recent advances in our understanding of purine release mechanisms, ectoenzymes that metabolize purines (CD38, CD39, CD73, ENPP1, and ENPP2/autotaxin), and signaling by key P2 purinergic receptors (P2X7, P2Y2, and P2Y12). In addition to metabolizing ATP or NAD +, some purinergic ectoenzymes metabolize other inflammatory modulators, notably lysophosphatidic acid and cyclic GMP-AMP (cGAMP). Also discussed are extracellular signaling effects of NAD +mediated by ADP-ribosylation, and epigenetic effects of intracellular adenosine mediated by modification of S-adenosylmethionine-dependent DNA methylation.

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          GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

          Lorenzo Sborgi, Sebastian Ruhl, Estefania Mulvihill … (2016)
          Abstract Pyroptosis is a lytic type of cell death that is initiated by inflammatory caspases. These caspases are activated within multi‐protein inflammasome complexes that assemble in response to pathogens and endogenous danger signals. Pyroptotic cell death has been proposed to proceed via the formation of a plasma membrane pore, but the underlying molecular mechanism has remained unclear. Recently, gasdermin D (GSDMD), a member of the ill‐characterized gasdermin protein family, was identified as a caspase substrate and an essential mediator of pyroptosis. GSDMD is thus a candidate for pyroptotic pore formation. Here, we characterize GSDMD function in live cells and in vitro. We show that the N‐terminal fragment of caspase‐1‐cleaved GSDMD rapidly targets the membrane fraction of macrophages and that it induces the formation of a plasma membrane pore. In vitro, the N‐terminal fragment of caspase‐1‐cleaved recombinant GSDMD tightly binds liposomes and forms large permeability pores. Visualization of liposome‐inserted GSDMD at nanometer resolution by cryo‐electron and atomic force microscopy shows circular pores with variable ring diameters around 20 nm. Overall, these data demonstrate that GSDMD is the direct and final executor of pyroptotic cell death.
          Article 0 comments Cited 491 times – based on 0 reviews     Review now
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            The P2Y12 receptor regulates microglial activation by extracellular nucleotides.

            Sharon E Haynes, Gunther Hollopeter, Guang Yang … (2006)
            Microglia are primary immune sentinels of the CNS. Following injury, these cells migrate or extend processes toward sites of tissue damage. CNS injury is accompanied by release of nucleotides, serving as signals for microglial activation or chemotaxis. Microglia express several purinoceptors, including a G(i)-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking G(i)-coupled P2Y(12) receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry(12)(-/-) mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y(12) expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y(12) is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.
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              DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity.

              Anetta Härtlová, Saskia Erttmann, Faizal Raffi … (2015)
              Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.
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                Author and article information

                Journal
                Title: Annual Review of Immunology
                Abbreviated Title: Annu. Rev. Immunol.
                Publisher: Annual Reviews
                ISSN (Print): 0732-0582
                ISSN (Electronic): 1545-3278
                Publication date Created: April 26 2019
                Publication date (Print): April 26 2019
                Volume: 37
                Issue: 1
                Pages: 325-347
                Affiliations
                [1 ]Division of Developmental Immunology, La Jolla Institute for Immunology, La Jolla, California 92037, USA;
                [2 ]Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA
                [3 ]Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany;
                [4 ]Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33136, USA;
                Article
                DOI: 10.1146/annurev-immunol-051116-052406
                PubMed ID: 30676821
                SO-VID: 744d9053-ebeb-4301-97f1-186a1f2fc0d8
                Copyright © © 2019
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