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Immune cell regulation by autocrine purinergic signalling

Key Points

  • Many different components facilitate autocrine purinergic signalling, including pannexin 1 hemichannels (which facilitate ATP release), P2X and P2Y receptors (which respond to ATP), ectonucleotidases (which hydrolyse ATP to adenosine), P1 receptors (which respond to adenosine) and nucleoside transporters and adenosine deaminase (which remove adenosine).

  • Different immune cells express distinct purinergic signalling components, and this has an important role in providing signal amplification following cell activation. The positive autocrine feedback loops mediated by purinergic signalling are essential for gradient sensing by phagocytes and antigen recognition by T cells.

  • When released from damaged, dying and apoptotic cells, ATP can serve as a danger signal that stimulates the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome, promotes chemotaxis of microglia, and boosts activation of other immune cell types that are recruited to sites of inflammation and tissue damage. High ATP concentrations at sites of inflammation trap neutrophils and other phagocytes by interfering with their autocrine purinergic chemotaxis signalling systems.

  • ATP release and autocrine purinergic signalling can amplify activation signals in immune cells but can also downregulate immune cell responses, either by activating suppressive P2 receptors or through adenosine formation and activation of suppressive A2A receptors.

  • A growing arsenal of pharmacological agents is available to modulate purinergic signalling in immune cells. The most widely investigated drugs target P1 receptors or the molecular processes that control the availability of the P1 receptor ligand adenosine.

Abstract

Stimulation of almost all mammalian cell types leads to the release of cellular ATP and autocrine feedback through a diverse array of purinergic receptors. Depending on the types of purinergic receptors that are involved, autocrine signalling can promote or inhibit cell activation and fine-tune functional responses. Recent work has shown that autocrine signalling is an important checkpoint in immune cell activation and allows immune cells to adjust their functional responses based on the extracellular cues provided by their environment. This Review focuses on the roles of autocrine purinergic signalling in the regulation of both innate and adaptive immune responses and discusses the potential of targeting purinergic receptors for treating immune-mediated disease.

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Figure 1: Components of autocrine purinergic signalling systems.
Figure 2: Purinergic signal amplification regulates neutrophil chemotaxis.
Figure 3: Regulation of phagocyte chemotaxis by autocrine and paracrine purinergic signalling mechanisms.
Figure 4: Purinergic signalling in T cell activation.

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Acknowledgements

I acknowledge with great appreciation the work of my many colleagues in this field, even though much of their important work could not be cited here. I also thank my co-workers and colleagues. Special gratitude goes to Y. Chen, L. Yip, T. Woehrle, Y. Inoue, Y. Sumi and N. Hashiguchi, and to my close collaborators S. Robson and P. Insel. I also acknowledge the major funding sources that have supported the work in my laboratory: US National Institutes of Health grants GM-51477, GM-60475, AI-072287, AI-080582 and Congressionally Directed Medical Research Programs grant PR043034.

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Glossary

Immune synapse

A large junctional structure that is formed at the cell surface between a T cell and an antigen-presenting cell. It is also known as the supramolecular activation cluster. Important molecules that are involved in T cell activation — including the T cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site. Immune synapses are now known to also form between other types of immune cells; for example, between dendritic cells and natural killer cells.

Find-me signal

A signal emitted by dying cells to promote the recruitment of scavenger cells, which clear the apoptotic cell body.

Inflammasome

A large multiprotein complex comprising an NLR (NOD-like receptor), the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD; also known as PYCARD) and pro-caspase 1. The assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 to generate the active pro-inflammatory cytokines.

Connexin and pannexin hemichannels

Channels in the cell membrane formed from either connexin or pannexin molecules. Two hemichannels on adjacent cells can interact to form a gap junction, which allows intercellular communication by enabling the exchange of cytosolic molecules between the adjoining cells. In individual cells, connexin and pannexin hemichannels can facilitate the release of cellular ATP into the extracellular space.

Inside-out signalling

The process by which intracellular signalling mechanisms result in the activation of cell surface receptors, such as integrins. By contrast, outside-in signalling is the process by which ligation of a cell surface receptor activates signalling pathways inside the cell.

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Junger, W. Immune cell regulation by autocrine purinergic signalling. Nat Rev Immunol 11, 201–212 (2011). https://doi.org/10.1038/nri2938

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