Trends in Immunology
Volume 25, Issue 1, January 2004, Pages 33-39
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Adenosine: an endogenous regulator of innate immunity

https://doi.org/10.1016/j.it.2003.11.003Get rights and content

Abstract

Although inflammatory and immunological reactions protect the host from invasion by microorganisms and eliminate debris at sites of tissue injury, they can also be responsible for significant tissue damage. Thus, regulatory mechanisms that limit damage from an overly exuberant immune response have evolved. It is increasingly apparent that adenosine, a purine nucleoside that is elaborated at injured and inflamed sites, has a central role in the regulation of inflammatory responses and in limiting inflammatory tissue destruction. Adenosine, called a ‘retaliatory metabolite’ because it is a regulatory autocoid that is generated as a result of cellular injury or stress, interacts with specific G protein-coupled receptors on inflammatory and immune cells to regulate their function. The effects of adenosine, acting at its receptors, on the functions of the cells that mediate innate immune responses, will be reviewed.

Section snippets

Adenosine bioavailability is a key determinant of adenosine action in the innate immune system

Physiological actions of adenosine almost exclusively result from its occupancy of cell surface adenosine receptors and the activation of downstream intracellular pathways. Processes related to its production, release, cellular uptake and metabolism determine the bioavailability of adenosine at receptor sites. These processes are closely interdependent and highly regulated. One good example for this interdependence is the concerted action of intracellular purinergic metabolic pathways, which

Immune cell trafficking between tissue compartments is regulated by endothelial adenosine receptors

Endothelial cells have multiple roles in inflammation and innate immunity. Indeed, the first events recognized as inflammation are mediated solely or in large measure by endothelial cells. In response to inflammatory mediators, ranging from complement components and immune complexes to cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), endothelial cells express adhesion molecules, which are responsible for the recruitment of leukocytes to inflamed sites. Endothelial

Neutrophils: crucial players in the early protective effect of adenosine against ischemic and inflammatory tissue injury

Neutrophils are the first inflammatory cells to be recruited to sites of injury and inflammation. These cells, the footsoldiers of the innate immune system, kill microorganisms, eliminate debris remaining after injury and release factors responsible for the recruitment of other inflammatory cells. Although these cells are crucial for preventing dissemination of infections, if unchecked they can also be responsible for significant tissue injury.

Soon after adenosine receptors were described,

Interaction of adenosine receptor signaling and pattern recognition receptor transduction pathways in APCs

Macrophages and dendritic cells (DCs) are specialized phagocytes that have an important role in the clearance of apoptotic host cells and injurious molecules, as well as in defense against infection. These antigen-presenting cells (APCs) are widely dispersed throughout the body, including at portals of entry to microorganisms. They participate in the initial capture and processing of antigens and then in the activation of specific lymphocyte-effector mechanisms. These activated lymphocytes in

Adenosine in mast cells a double-edged sword?

Mast cells have traditionally been associated with IgE-mediated immune responses against parasites, however, mast cells are now generally recognized as essential components of innate immune responses against bacteria and can also have a role in the pathogenesis of inflammatory arthritis [44]. Interestingly, mast cells could represent the exception to the ‘rule’ that adenosine is tissue protective and immunosuppresive because adenosine is a potent stimulator of mast-cell function. Adenosine,

Adenosinergic therapy of inflammatory diseases

Based on the evidence summarized, adenosine appears to promote a self-limiting, healthy immune response. Early after the injurious or infectious signal, high concentrations of extracellular adenosine favor a transition from neutrophil infiltration to DC recruitment, providing a framework in which less sophisticated defense mechanisms represented by neutrophils give way to a highly efficient specific immune response initiated by DCs. At later stages of immune or inflammatory processes, adenosine

Acknowledgements

This work was supported by National Institutes of Health grants GM66189 (G.H.), AR41911, GM56268, AA13336 (B.NC.); a grant from King Pharmaceuticals Inc. (B.N.C.); a General Clinical Research Center grant from NIH, NCRR (M01RR00096 to B.N.C.) and by the Kaplan Cancer Center (B.N.C.).

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