A2B Adenosine Receptor Blockade Enhances Macrophage-Mediated Bacterial Phagocytosis and Improves Polymicrobial Sepsis Survival in Mice

Belikoff, Bryan; Hatfield, Stephen; Georgiev, Peter; Ohta, Akio; Lukashev, Dmitriy; Buras, Jon A.; Remick, Daniel G.; Sitkovsky, Michail V.

doi:10.4049/jimmunol.1001567

Cited by 86 publications

(97 citation statements)

References 49 publications

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“…Our data are consistent with previous reports suggesting a role for A2bR-mediated immunosuppression [48][49][50] and implicating the A2aR as the major adenosine receptor involved in IL-10 induction in macrophages. 51 Interestingly, both the A2aR and A2bR are G-protein coupled receptors associated with the Gas subunit and are capable of activating adenylate cyclase and enhancing intracellular cyclic AMP (cAMP) levels.…”

Section: Discussionsupporting

confidence: 83%

TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses

Cohen

Briggs

Marino

et al. 2013

Blood

124

140

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• TLR-stimulated macrophages synthesize, release, and hydrolyze ATP via CD39 to regulate their own activation state.• The loss of macrophage CD39 prevents regulatory macrophage development and leads to lethal inflammatory responses and septic shock in mice.Sepsis is a highly fatal disease caused by an initial hyperinflammatory response followed by a state of profound immunosuppression. Although it is well appreciated that the initial production of proinflammatory cytokines by macrophages accompanies the onset of sepsis, it remains unclear what causes the transition to an immunosuppressive state. In this study, we reveal that macrophages themselves are key regulators of this transition and that the surface enzyme CD39 plays a critical role in self-limiting the activation process. We demonstrate that Toll-like receptor (TLR)-stimulated macrophages modulate their activation state by increasing the synthesis and secretion of adenosine triphosphate (ATP). This endogenous ATP is paradoxically immunosuppressive due to its rapid catabolism into adenosine by CD39. Macrophages lacking CD39 are unable to transition to a regulatory state and consequently continue to produce inflammatory cytokines. The importance of this transition is demonstrated in a mouse model of sepsis, where small numbers of CD39-deficient macrophages were sufficient to induce lethal endotoxic shock. Thus, these data implicate CD39 as a key "molecular switch" that allows macrophages to self-limit their activation state. We propose that therapeutics targeting the release and hydrolysis of ATP by macrophages may represent new ways to treat inflammatory diseases. (Blood. 2013;122(11):1935-1945 IntroductionFailure to control inflammatory macrophage activation responses can lead to pathological diseases, best exemplified by sepsis. Despite our growing understanding of its pathogenesis, sepsis continues to affect more than 200 000 people annually in the United States, with a mortality rate as high as 50%.1,2 The severe pathology associated with sepsis occurs in response to the hyperproduction of macrophagederived inflammatory cytokines, which can lead to vascular and tissue destruction, multiple organ failure, shock, and death.3 Intriguingly, macrophages isolated from late-stage septic individuals exhibit the phenotype of immunosuppressive, regulatory macrophages, expressing high levels of the anti-inflammatory cytokine interleukin-10 (IL-10) and low levels of tumor necrosis factor a (TNF-a) and IL-12. [4][5][6] These observations suggest the transition from inflammatory to immunosuppressive macrophages may be critical to control initial inflammatory responses and prevent lethal septic shock. 4,7,8 However, the molecular mechanism by which this transition is achieved remains poorly understood.In the present work, we examine the role that endogenous CD39 and adenosine triphosphate (ATP) play in regulating the macrophage inflammatory response. Recently, extracellular ATP (eATP) has been characterized as a "danger signal" that can promote inflammation through ...

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Section: Discussionsupporting

confidence: 83%

TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses

Cohen

Briggs

Marino

et al. 2013

Blood

124

140

View full text Add to dashboard Cite

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“…We did not observe an increase in oxidative burst in A 2B R-deficient neutrophils; our results may represent cross-talk between neutrophil adenosine receptors, with maintenance of A 2A R signaling in A 2B R -/-neutrophils, because A 2A R activation strongly inhibits oxidative burst (9,18). Our study also relates to work demonstrating that A 2B R-deficient macrophages exhibit enhanced phagocytosis and bacterial clearance in a model of sepsis (35). This study concluded that A 2B R -/-neutrophils did not demonstrate enhanced antibacterial activity, but only phagocytic capacity as a measure of bactericidal activity.…”

Section: Discussionsupporting

confidence: 63%

“…Studies of adenosine receptor signaling in animal models of intraperitoneal sepsis have reported contradictory findings: A 2B R deletion was found to increase expression of inflammatory cytokines and worsened survival (40); conversely, A 2B R blockade, global deletion, or selective deletion from myeloid cells was associated with accelerated bacterial clearance and improved outcome (35). Because unchecked inflammation and failure to control infection can both lead to death, minor differences in experimental protocols might influence the outcome of such experiments.…”

Section: Discussionmentioning

confidence: 98%

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Barletta¹,

Cagnina

Burdick

et al. 2012

Am J Respir Crit Care Med

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Rationale: Activation of the adenosine A 2B receptor (A 2B R) promotes antiinflammatory effects in diverse biological settings, but the role of this receptor in antimicrobial host defense in the lung has not been established. Gram-negative bacillary pneumonia is a common and serious illness associated with high morbidity and mortality, the treatment of which is complicated by increasing rates of antibiotic resistance. Objectives: To test the hypothesis that absence of adenosine A 2B receptor signaling promotes host defense against bacterial pneumonia. Methods: We used a model of Klebsiella pneumoniae pneumonia in wild-type mice and mice with targeted deletion of the A 2B R. Host responses were compared in vivo and leukocyte responses to the bacteria were examined in vitro. Measurements and Main Results: A 2B R -/-mice demonstrated enhanced bacterial clearance from the lung and improved survival after infection with K. pneumoniae compared with wild-type controls, an effect that was mediated by bone marrow-derived cells. Leukocyte recruitment to the lungs and expression of inflammatory cytokines did not differ between A 2B R -/-and wild-type mice, but A 2B R -/-neutrophils exhibited sixfold greater bactericidal activity and enhanced production of neutrophil extracellular traps compared with wild-type neutrophils when incubated with K. pneumoniae. Consistent with this finding, bronchoalveolar lavage fluid from A 2B R -/-mice with Klebsiella pneumonia contained more extracellular DNA compared with wild-type mice with pneumonia. Conclusions: These data suggest that the absence of A 2B R signaling enhances antimicrobial activity in gram-negative bacterial pneumonia.Keywords: neutrophil; extracellular traps; pneumonia; adenosine Pneumonia is a leading cause of hospitalization in the United States and is the most common infectious cause of death (1, 2). Aerobic gram-negative bacilli are the most common cause of health care-associated pneumonia; mortality rates from gram-negative pneumonia range from 30 to 60% with antimicrobial therapy (3, 4). The emergence of multiresistant strains of gram-negative bacteria, combined with limited development of new antimicrobial therapies, has exacerbated the need for new approaches to combating these pathogens (5-7). Therapy aimed at augmenting the host response has the potential to enhance bacterial clearance and improve outcomes, and could provide a new avenue for therapeutic advances in combating gramnegative pneumonia, including infections that are caused by antibiotic-resistant pathogens.Adenosine, a breakdown product of ATP, is a potent signaling molecule released from a variety of cells to dampen inflammation, limit tissue destruction, and promote repair (8, 9). In response to cellular stress or tissue injury, the extracellular concentration of adenosine can increase 100-fold. Adenosine acts on four widely expressed G protein-coupled receptors: A 1 , A 2A , A 2B , and A 3 , with variable expression among different cells. The adenosine A 2B receptor (A 2B R) has been shown to en...

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“…Adora2b signaling, we next performed studies to identify the role of Adora2b expressed on different cell types. As previous studies had implicated Adora2b signaling on endothelia (32) or epithelia (33) in organ inflammation, we used a transgenic mouse line with a floxed Adora2b gene (34) . Indeed, mice with genetic deletion of the Adora2b in tubular epithelia retained dipyridamole-mediated kidney protection from ischemia, indicating that ENT inhibition-mediated kidney protection is independent of Adora2b expression on tubular epithelia ( Figure 9, A-E).…”

Section: Figurementioning

confidence: 99%

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Grenz¹,

Bauerle²,

Dalton³

et al. 2012

J. Clin. Invest.

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114

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A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) -a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1 -/-mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications. IntroductionAcute kidney injury (AKI) is clinically defined by an abrupt reduction in kidney function (e.g., a decrease in glomerular filtration rate [GFR]), occurring over a period of minutes to days. AKI is frequently caused by an obstruction of renal blood flow (renal ischemia) and represents an important cause of morbidity and mortality of patients (1-3). Indeed, a recent study revealed that only a mild increase (0.3 mg/dl) in the serum creatinine level is associated with a 70% greater risk of death than in patients without this increase (2, 3). Particularly for surgical patients, AKI represents a significant threat. For example, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a rate of AKI of up to 30% (4). Similarly, AKI after cardiac surgery occurs in up to 10% of patients under normal circumstances and is associated with dramatic increases in mortality (5). In addition, patients with sepsis frequently go on to develop AKI, and the combination of moder-

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A2B Adenosine Receptor Blockade Enhances Macrophage-Mediated Bacterial Phagocytosis and Improves Polymicrobial Sepsis Survival in Mice

Cited by 86 publications

References 49 publications

TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses

TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses

Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

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A2B Adenosine Receptor Blockade Enhances Macrophage-Mediated Bacterial Phagocytosis and Improves Polymicrobial Sepsis Survival in Mice

Cited by 86 publications

References 49 publications

TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses

TLR stimulation initiates a CD39-based autoregulatory mechanism that limits macrophage inflammatory responses

Adenosine A2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

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Adenosine A_2BReceptor Deficiency Promotes Host Defenses against Gram-Negative Bacterial Pneumonia