Adenosine Deamination Sustains Dendritic Cell Activation in Inflammation

Abstract

Adenosine is a suppressive agent that protects the host from excessive tissue injury associated with strong inflammation. In tissue stress, higher levels of adenosine signal through adenosine receptors to exert strong anti-inflammatory effects, and thus protect host cells. Existing evidence also suggests that elevated adenosine potently down-regulates the activation of lymphocytes during inflammation. This notion, however, is in contrast with another basic observation that the immune system is highly activated precisely under the same circumstances against pathogens. In this study, we show that inflammatory responses of dendritic cells (DCs) are highly sensitive to adenosine suppression. However, they intrinsically carry high adenosine deaminase activity, which in turn degrades and removes adenosine from the surroundings, cutting off DCs from the suppression. This regulatory mechanism is important in DC responses to pathogen-associated molecular patterns and their activation of T cells. Our findings suggest a mechanism that DCs maintain their hyperreactive state in inflammation despite the general state of suppression, and reveal a regulatory role of adenosine deaminase in DC innate immune responses.

High Levels of Adenosine Deaminase on Dendritic Cells Promote Autoreactive T Cell Activation and Diabetes in Nonobese Diabetic Mice

“…Tregs use CD39 and CD73 to actively remove ATP, an immune activator, and convert it into adenosine for the suppression of other T cells. Similar suppressive effects are seen with macrophages and DCs (9)(10)(11)(12). However, how adenosine is handled in immune activation is rather complex.…”

“…This enzyme converts adenosine into inosine, for further processing into xanthine/hypoxanthine and uric acid. In fact, because adenosine-mediated suppression is strong, the presence of ADA is essential for some immune activation to take place (9,10). On T cells, the presence of surface ADA enhanced their activation (13)(14)(15).…”

Antiproliferative effects of selective adenosine receptor agonists and antagonists on human lymphocytes: evidence for receptor-independent mechanisms

“…The effects of adenosine on lymphocytes are of particular interest since the accumulation of extracellular and intracellular adenosine and 2′-deoxyadenosine in the absence of adenosine deaminase (ADA) activity is lymphotoxic and causes SCID [12,13], which is characterized by a loss of function and depletion of T and B lymphocytes [14]. Part of this effect may be attributed to adenosine via the activation of ARs and sustained increase in cAMP levels [5].…”

Disordered Lymphoid Purine Metabolism Contributes to the Pathogenesis of Persistent Borrelia garinii Infection in Mice

“…For instance, dendritic cells remove adenosine from their environment via high intrinsic ADA activity, which allows cutting them off from the suppression and mediating T cell activation and other inflammatory responses (7). Despite this general trend, NTPDase1/CD39 and ecto-59-nucleotidase/CD73 can be selectively upregulated on a certain population of activated CD4 + CD25 + Foxp3 + T reg cell lymphocytes, thereby protecting these immunosuppressive cells from cytotoxic effects of extracellular ATP (30) and contributing to the control of inflammatory autoimmune diseases (8,29).…”

“…In turn, adenosine generated in the course of ATP hydrolysis has a nonredundant counteracting role in attenuating the inflammation and tissue damage. Specific immunosuppressive functions of adenosine include inhibition of TNF-a, IL-1, IL-6, and IL-12 synthesis by lymphoid cells (2,7,8), maintenance of vascular endothelial barrier integrity, and control of lymphocyte trafficking between the blood and tissues (5,9,10). These effects are mediated through G proteincoupled adenosine receptors, which function either by activating (A 2A and A 2B ) or inhibiting (A 1 and A 3 ) adenylate cyclase (6,8).…”