Journal Article

Immune cell regulation by autocrine purinergic signalling

Junger, Wolfgang G.

2011

Overview

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. Here, Wolfgang Junger discusses the importance of purinergic receptor signalling for fine-tuning immune cell responses. Autocrine signalling through purinergic receptors can both amplify and inhibit leukocyte functions; the author explains how this is important for sensing chemotactic gradients and detecting rare antigens. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/2152 / 631/250/516 / 692/700/565/1436/2185 / Adaptive Immunity - physiology / Adenosine / Adenosine - metabolism / Adenosine triphosphate / Adenosine Triphosphate - metabolism / Adenosine Triphosphate - physiology / Adenosine Triphosphate - secretion / Animals / ATP / Autocrine Communication - physiology / Biomedical and Life Sciences / Biomedicine / Cells / Cellular signal transduction / Chemotaxis - physiology / Cytokines / Humans / Immune response / Immune Tolerance - physiology / Immunity, Innate - physiology / Immunology / Leukocytes - immunology / Leukocytes - metabolism / Lymphocyte Activation - physiology / Lymphocytes / Lymphocytes - immunology / Lymphocytes - metabolism / Macrophages - physiology / Mammals / Nod Signaling Adaptor Proteins - physiology / Nucleoside Transport Proteins - physiology / Physiological aspects / Physiology / Pyrophosphatases - physiology / Receptors, Purinergic - physiology / review-article / Signal Transduction - immunology / Toll-Like Receptors - physiology