Purinergic regulation of the immune system

Journal name:
Nature Reviews Immunology
Volume:
16,
Pages:
177–192
Year published:
DOI:
doi:10.1038/nri.2016.4
Published online

Abstract

Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.

At a glance

Figures

  1. Three temporal phases of purinergic signalling following tissue injury.
    Figure 1: Three temporal phases of purinergic signalling following tissue injury.

    In response to tissue injury, there is an acute phase of ATP release from stressed or damaged cells that results in a high ratio of ATP/adenosine. ATP and other nucleotides activate P2 purinergic receptors that stimulate chemotaxis and activation of immune cells. A second subacute phase of inflammation is associated with reduced ATP release and the induction of ectonucleotidases that decrease the ATP/adenosine ratio. In addition, the induction of adenosine receptors on activated or hypoxic immune cells increases their sensitivity to adenosine. These events limit the extent and duration of the inflammatory response. A third chronic phase of inflammation following tissue injury is associated with a low ATP/adenosine ratio and persistent adenosine receptor activation on parenchymal cells and tissue-resident macrophages. The resultant activation of A2B adenosine receptors (A2BRs) produces persistent low-grade inflammation, fibrosis and angiogenesis. DC, dendritic cell; IL-6, interleukin-6; NK cell, natural killer cell; P2X7R, P2X7 purinergic receptor; TH17 cell, T helper 17 cell; TReg cell, regulatory T cell; VEGF, vascular endothelial growth factor.

  2. Purinergic signalling in T cells.
    Figure 2: Purinergic signalling in T cells.

    a | In naive T cells, low-strength T cell receptor (TCR) activation stimulates proliferation but strong activation causes apoptosis owing to a reduction in the expression of interleukin-7 receptors (IL-7Rs) that are necessary for T cell survival. By dampening the TCR signalling cascade, A2A adenosine receptor (A2AR) engagement can enhance naive T cell survival by maintaining IL-7R expression. b | In effector T cells, extracellular ATP stimulates Ca2+ entry through P2X purinergic receptor (P2XR) channels and Ca2+ mobilization (P2YR) to facilitate Ca2+–calmodulin (CAM)-dependent activation and nuclear translocation of nuclear factor of activated T cells (NFAT), which stimulates the production of IL-2, pannexin 1 channels and other NFAT targets. Autocrine ATP release helps to sustain P2 purinergic receptor signalling and NFAT activation. Extracellular adenosine and inhibitors of phosphodiesterase isozyme 4 (PDE4) elevate cAMP and activate protein kinase A (PKA), which activates C-terminal SRC kinase (CSK), a negative regulator of LCK. This attenuates the activation of transcription factors that are downstream of TCR activation, including NFAT, nuclear factor-κB (NF-κB) and AP-1. TCR activation increases A2ARs through NF-κB-dependent induction. c | In regulatory T cells, high expression of cell surface CD39 and CD73 rapidly converts locally produced pro-inflammatory ATP to anti-inflammatory adenosine. IL-6 signalling enhances the autocrine production and release of ATP. High levels of ATP or NAD+ can stimulate apoptosis owing to pore formation by P2X7Rs. Adenosine activates A2ARs and increases the expression of CD39, CD73, programmed cell death protein 1 (PD1) and forkhead box P3 (FOXP3). CREB, cAMP-responsive element-binding protein; CTLA4, cytotoxic T lymphocyte antigen 4; DAG, dystrophin-associated glycoprotein; ERK, extracellular signal-regulated kinase; FOXO1, forkhead box O1; JAK, Janus kinase; JNK, JUN N-terminal kinase; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PLCγ1, phospholipase Cγ1; RACK, receptor for activated C-kinase; STAT5, signal transducer and activator of transcription 5; TGFβ, transforming growth factor-β.

  3. Purinergic signalling in iNKT cells.
    Figure 3: Purinergic signalling in iNKT cells.

    Sterile tissue injury resulting from tissue ischaemia or tissue transplantation results in the release of damage-associated molecular patterns (DAMPs), such as ATP and high mobility group box 1 (HMGB1), that enhance the production in antigen-presenting cells (APCs) of CD1d-restricted lipid antigens and co-stimulatory cytokines (interleukin-12 (IL-12) and IL-18). Lipid antigens, IL-12, IL-18 and ATP stimulate invariant natural killer T (iNKT) cells to produce a mixture of pro-inflammatory (interferon-γ (IFNγ)) and anti-inflammatory (IL-4 and IL-13) cytokines. IFNγ stimulates the production of IFNγ-inducible cytokines (CXC-chemokine ligand 9 (CXCL9), CXCL10 and CXCL11) that are chemotactic to neutrophils. iNKT cell activation causes the induction of A2A adenosine receptors (A2ARs) and CD39 to enhance adenosine signalling through A2ARs. A2AR activation inhibits IFNγ production and stimulates IL-4 and IL-13 production, accelerates the conversion of ATP to adenosine and inhibits tissue inflammation and injury. ; P2X7R, P2X7 purinergic receptor; TCR, T cell receptor; TLR, Toll-like receptor.

  4. Purinergic signalling in monocytes and macrophages.
    Figure 4: Purinergic signalling in monocytes and macrophages.

    a | In monocytes, ATP and UTP released from inflamed tissues are chemotactic to monocytes, activate nuclear factor-κB (NF-κB) and favour monocyte polarization into pro-inflammatory (M1) macrophages. Adenosine signalling through A2A adenosine receptors (A2ARs) and A2BRs activates nuclear receptor subfamily 4 group A (NR4A) transcription factors that inhibit NF-κB activation and favour monocyte polarization into anti-inflammatory (M2) macrophages. A2AR and A2BR signalling increase levels of cAMP and Ca2+, which, along with hypoxia, increases angiogenesis by induction of vascular endothelial growth factor (VEGF). Protein kinase A (PKA) and cAMP-responsive element-binding protein (CREB)-dependent activation of CCAAT/enhancer-binding protein-β (C/EBPβ) increases anti-inflammatory interleukin-10 (IL-10) production. b | In macrophages, activation of P2X7 purinergic receptors (P2X7Rs) by ATP helps to activate the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome and caspase 1 to trigger the proteolytic maturation of IL-1β and other cytokines. Engulfment of apoptotic cells by macrophages stimulates the production of cytokines (CXCL1 and CXCL2) that are chemotactic to neutrophils. Chemokine production is regulated by inhibitory A2ARs and stimulatory A3Rs. DAMP, damage-associated molecular pattern; STAT1, signal transducer and activator of transcription 1; TLR, Toll-like receptor; TNF, tumour necrosis factor; TRIF, TIR domain-containing adaptor protein inducing IFNβ.

  5. Purinergic signalling in neutrophils.
    Figure 5: Purinergic signalling in neutrophils.

    In neutrophils, ATP, UPT and other nucleotides released from inflamed tissues are directly chemotactic and stimulate the production of chemotactic cytokines. Adenosine signals through A2A adenosine receptors (A2ARs) to inhibit production of cytokines, inhibit superoxide production by NADPH oxidase and decrease the expression of adhesion molecules such as α4β1 integrin. IL-17, interleukin-17; PKA, protein kinase A; TNF, tumour necrosis factor.

  6. Purinergic signalling in the tumour microenvironment.
    Figure 6: Purinergic signalling in the tumour microenvironment.

    The solid tumour microenvironment is persistently inflamed and hypoxic and has high levels of ATP and adenosine. Most tumour cell express high levels of P2X7 purinergic receptors (P2X7Rs), which stimulate cell proliferation, and of A2B adenosine receptors (A2BRs) that stimulate cell dispersal and metastasis. Myeloid lineage cells such as macrophages and dendritic cells are influenced by ATP binding to P2X7Rs to adopt a pro-inflammatory (M1) phenotype. Myeloid cells are influenced by adenosine binding to A2ARs and A2BRs to adopt an anti-inflammatory (M2) phenotype that inhibits immune killing of tumours. A2BR signalling also enhances tumour angiogenesis and fibrosis. Cytotoxic CD8+ T cell proliferation and killing ability in response to T cell receptor (TCR) activation is enhanced by P2X1R, P2X4R and P2Y12R signalling and inhibited by A2AR signalling. CAM, calmodulin; CSK, C-terminal SRC kinase; IL-6, interleukin-6; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor-κB; VEGF, vascular endothelial growth factor.

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Affiliations

  1. Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.

    • Caglar Cekic
  2. Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.

    • Joel Linden

Competing interests statement

J.L. owns equity in Adenosine Therapeutics, LLC and Lewis and Clark Pharmaceuticals. These companies are developing drugs that target adenosine receptors.

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  • Caglar Cekic

    Caglar Cekic is an assistant professor at Bilkent University, Ankara, Turkey. A key research interest of his group in immunopharmacology is to investigate low-toxicity immunomodulation through purinergic signalling and pattern-recognition receptors and to develop novel immunotherapies.

  • Joel Linden

    Joel Linden is a professor of developmental immunology at La Jolla Institute for Allergy and Immunology, California, USA. He is investigating the role of adenosine receptor signalling in the control of inflammation following tissue injury and the mechanism by which adenosine inhibits immune activation in the tumour microenvironment. He has published over 250 papers on the subject of adenosine, founded Adenosine Therapeutics, LLC, and is an inventor on 34 issued US patents. Joel Linden's homepage

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