The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors?

doi:10.1016/j.it.2005.04.004

Trends in Immunology

Volume 26, Issue 6, June 2005, Pages 299-304

https://doi.org/10.1016/j.it.2005.04.004 Get rights and content

Immune cells not only destroy pathogens but might also cause collateral injuries to normal tissues. The surprisingly low incidence of post-inflammatory complications is explained here by a ‘danger-sensing’ physiological mechanism that ensures the tissue-protecting negative feedback inhibition of overactive immune cells. We focus here on immunoregulatory influences of ‘non-immune’ signaling molecules in physiological and pathophysiological tissue microenvironments. We propose that hypoxia-associated accumulation of extracellular adenosine might be an important immunoregulatory signal. A2 receptors for extracellular adenosine might act as both primary sensors of excessive collateral tissue damage during an immune response and triggers of the emergency downregulation of overactive immune cells. Regulation by extracellular adenosine would protect normal organs from injury and/or re-direct immune responses.

Section snippets

Tightly controlled resolution of inflammation

The inflammatory processes are mediated by a variety of proinflammatory cytokines and cytotoxic molecules produced by immune cells, which destroy pathogens and virus-infected cells in highly functionally specialized compartments of vital organs. The structural organization of individual cells in tissues was evolutionary selected to efficiently perform specific functions and, although some degree of redundancy is built-in, these structures are fragile and are not designed to sustain the

Two danger signals

These considerations suggest that the regulation of the immune system requires at least two ‘danger’ signals (Figure 1). It is suggested that the first danger signal, which has been extensively discussed [3], indicates the presence of danger from pathogens, other injurious events or mutations that result in the death or scavenging of cells. This danger signal leads to the activation of immune cells and thereby evokes defensive effector functions 3, 4. In addition, there must be a second danger

A2 adenosine receptors and their role in the control of acute inflammation

Adenosine receptors belong to the P1 class of ‘purinergic’ receptors, which also include the P2 class of receptors that bind ATP [7]. Purinergic receptors have been studied since the early 1970s and have been implicated in a variety of physiological and pathological responses [7], including T-cell effector function 8, 9 and the initiation of immune cell activation [10].

We focus here on adenosine receptors. Advanced pharmacological probes 11, 12 and cDNA cloning [13] have led to the

Crucial factors in adenosinergic regulation

Although it is clear that the pharmacologically added adenosine can inhibit some forms of immunity, it is not clear whether this pathway is also a normal physiological mechanism by which a tissue could downregulate a destructive immune response. There are many Gs protein-coupled receptors [24] and some of their cAMP-elevating ligands, such as catecholamines, prostaglandins, dopamine and histamine, show immunosuppressive pharmacological effects and have been considered as potential

Concluding remarks

We propose that: (i) damaged microcirculation and the ensuing local tissue hypoxia in inflamed areas represent the primary events that indicate the excessive inflammation. The hypoxia then leads to the (ii) accumulation of extracellular adenosine, which represents the most immediate signal of tissue damage and the need to ‘de-activate’ immune cells. Adenosine is then (iii) ‘sensed’ by immunosuppressive Gs protein-coupled A2 adenosine receptors, which, in turn, (iv) inhibit immune cells (STOP

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Trends in Immunology

The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors?

Section snippets

Tightly controlled resolution of inflammation

Two danger signals

A2 adenosine receptors and their role in the control of acute inflammation

Crucial factors in adenosinergic regulation

Concluding remarks

Biochem. Pharmacol.

Immunol. Today

J. Biol. Chem.

Blood

J. Biol. Chem.

Methods Enzymol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Blood

Trends Immunol.

Trends Biochem. Sci.

Points of control in inflammation

Nature

The danger model: a renewed sense of self

Science

Toll-like receptor control of the adaptive immune responses

Nat. Immunol.

Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage

Nature

Physiological control of immune response and inflammatory tissue damage by hypoxia inducible factors and adenosine A2A receptors

Annu. Rev. Immunol.

50 years of passionate commitment

Cell. Mol. Life Sci.

Pharmacology of adenosine A2A receptors and therapeutic applications

Curr. Top. Med. Chem.

Development of selective purinoceptor agonists and antagonists

Selective amplification and cloning of four new members of the G-protein-coupled receptor family

Science

Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors

J. Exp. Med.

Animal models for the study of adenosine receptor function

J. Cell. Physiol.