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Purinergic regulation of the immune system

Key Points

  • ATP, ADP and other nucleotides can be released by stressed or apoptotic cells into the extracellular environment. They function as autocrine and paracrine signalling molecules by activating cell-surface purinergic receptors.

  • Activation of purinergic signalling pathways can have both pro- and anti-inflammatory effects.

  • During the acute stages of tissue injury, purinergic signalling can promote the recruitment and activation of leukocytes to the damaged site. At later times, purinergic signalling dampens inflammation and promotes wound healing.

  • Drugs that target purinergic receptors are being developed as potential therapeutics to treat patients with inflammatory disorders, autoimmune diseases or cancer.

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.

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Figure 1: Three temporal phases of purinergic signalling following tissue injury.
Figure 2: Purinergic signalling in T cells.
Figure 3: Purinergic signalling in iNKT cells.
Figure 4: Purinergic signalling in monocytes and macrophages.
Figure 5: Purinergic signalling in neutrophils.
Figure 6: Purinergic signalling in the tumour microenvironment.

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Authors and Affiliations

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Corresponding author

Correspondence to Joel Linden.

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Competing interests

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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Glossary

Inotropic

Ligand-gated channel type of receptor.

Metabotropic

G protein-coupled type of receptor.

Inflammasome

A multiprotein complex in myeloid cells that is activated upon cellular infection or stress and triggers the maturation of pro-inflammatory cytokines.

Spare receptors

Receptors that lead to an increase in the functional potency of a response to receptor occupancy by an agonist as a result of increased receptor expression.

Pannexins

A family of membrane- spanning proteins consisting of pannexin 1, pannexin 2 and pannexin 3. Pannexin 1 is widely expressed and oligomerizes into a hexamer to form a single membrane channel.

Endothelial nitric oxide synthase

(eNOS). A Ca2+–calmodulin-dependent enzyme that catalyses the production of the vasodilator nitric oxide (NO) in endothelial cells.

Phosphodiesterase isozyme 4

(PDE4). The predominant isoform of type 4 cAMP phosphodiesterase in immune cells.

CD1d-restricted

Natural killer T (NKT) cells that are activated by lipid antigens presented in the binding cleft of the MHC class Ib molecule CD1 d.

α-galactosylceramide

(αGalCer). A glycolipid antigen of invariant natural killer T (iNKT) cells.

Cytokine storm

A potentially fatal immune reaction that is associated with very high levels of cytokines.

Indoleamine 2,3-dioxygenase

(IDO). An enzyme that catalyses the rate-limiting first step in tryptophan catabolism and inhibits antitumour immune responses.

Mixed lymphocyte reactions

Proliferative responses of one individual's lymphocytes that are cultured in the presence of another individual's lymphocytes.

Graft-versus-host disease

(GVHD). An immune-mediated reaction that occurs following transplantation of bone marrow cells that attack the recipient.

Myeloid-derived suppressor cells

(MDSCs). Myeloid lineage cells that have strong immunosupressive activity.

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Cekic, C., Linden, J. Purinergic regulation of the immune system. Nat Rev Immunol 16, 177–192 (2016). https://doi.org/10.1038/nri.2016.4

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