Signaling through the A2B Adenosine Receptor Dampens Endotoxin-Induced Acute Lung Injury

Schingnitz, Ulrich; Hartmann, Katherine E; MacManus, Christopher F.; Eckle, Tobias; Zug, Stephanie; Colgan, Sean P.; Eltzschig, Holger K.

doi:10.4049/jimmunol.0903035

Cited by 162 publications

(184 citation statements)

References 55 publications

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“…Lung histology revealed similar degrees of consolidation with intraalveolar neutrophils in wild-type and A 2B R-deficient animals; bacteria were visible in wild-type but not A 2B R-deficient lungs ( Figure 2C). Because the A 2B R signaling has been linked to reduced extent of lung injury in several animal models, including in response to LPS (14,29), we also assessed the extent of lung injury in wild-type and A 2B R -/-mice with bacterial pneumonia; we found A 2B R-deficient mice with pneumonia to have reduced lung injury as compared with wild-type animals, a finding that we attribute to improved bacterial clearance (see Figure E2 in the online supplement).…”

Section: Deletion Of the A 2b R On Bone Marrow-derived Cells Results mentioning

confidence: 99%

“…The role of A 2B R in disease pathogenesis is highly complex, being determined by rates of local production and clearance of adenosine, the extent of expression of A 2B R by resident and recruited cells, and the repertoire of these cells for the other adenosine receptors, which compete with A 2B R for adenosine. A 2B R signaling has been reported to be broadly antiinflammatory in several models of acute lung injury; in particular, A 2B R deficiency is associated with increased lung inflammation after challenge with bleomycin, LPS, ischemia-reperfusion, and ventilator-associated lung injury (29,(36)(37)(38). The reported mechanisms of these effects have varied markedly between these models and have included alteration of leukocyte traffic, reduction in vascular permeability mediated by bone marrow-derived cells, and attenuation of the neutrophil oxidative burst (14,37,38); on the other hand, work has shown A 2B R expression on bone marrow-derived cells to paradoxically enhance neutrophil migration to the lung interstitium in response to LPS (39).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Deletion Of the A 2b R On Bone Marrow-derived Cells Results mentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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“…As such, A2BAR activation is involved in the inflammatory response of mast cells, epithelial cells, smooth muscle cells, and fibroblasts (30,31). A2BAR also limits an inflammatory response of the endothelium, determines its permeability, and suppresses macrophage activation, thereby preventing tissue injury after episodes of hypoxia and ischemia (32,33). Thus, A2BAR might be an important pharmacological target in treating conditions associated with barrier dysfunction and acute inflammation.…”

Section: A2barmentioning

confidence: 99%

Netrin-1 Signaling Dampens Inflammatory Peritonitis

Mirakaj

Gatidou

Pötzsch

et al. 2011

The Journal of Immunology

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Previous studies implicated the anti-inflammatory potential of the adenosine 2B receptor (A2BAR). A2BAR activation is achieved through adenosine, but this is limited by its very short t1/2. To further define alternative adenosine signaling, we examined the role of netrin-1 during acute inflammatory peritonitis. In this article, we report that animals with endogenous repression of netrin-1 (Ntn1+/−) demonstrated increased cell count, increased peritoneal cytokine concentration, and pronounced histological changes compared with controls in a model of zymosan A peritonitis. Exogenous netrin-1 significantly decreased i.p. inflammatory changes. This effect was not present in animals with deletion of A2BAR (A2BAR−/−). A2BAR−/− animals demonstrated no change in cell count, i.p. cytokine concentration, or histology in response to netrin-1 injection. These data strengthen the role of netrin-1 as an immunomodulatory protein exerting its function in dependence of the A2BAR and further define alternative adenosine receptor signaling.

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“…For example, extracellular adenosine generation and signaling appears to be protective during the acute phase of lung injury, but has been implicated in promoting a fibrotic response during chronic forms of lung disease. [33][34][35][36][37] Diabetic nephropathy is among the leading causes of morbidity and mortality in patients with diabetes mellitus. It belongs to the group of CKDs and is characterized by its progressive nature, eventually leading to nephrotic syndrome and diffuse glomerulosclerosis.…”

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confidence: 99%

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

Tak¹,

Ridyard²,

Kim

et al. 2014

Journal of the American Society of Nephrology

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Nucleotide phosphohydrolysis by the ecto-59-nucleotidase (CD73) is the main source for extracellular generation of adenosine. Extracellular adenosine subsequently signals through four distinct adenosine A receptors (Adora1, Adora2a, Adora2b, or Adora3). Here, we hypothesized a functional role for CD73-dependent generation and concomitant signaling of extracellular adenosine during diabetic nephropathy. CD73 transcript and protein levels were elevated in the kidneys of diabetic mice. Genetic deletion of CD73 was associated with more severe diabetic nephropathy, whereas treatment with soluble nucleotidase was therapeutic. Transcript levels of renal adenosine receptors showed a selective induction of Adora2b during diabetic nephropathy. In a transgenic reporter mouse, Adora2b expression localized to the vasculature and increased after treatment with streptozotocin. Adora2b 2/2 mice experienced more severe diabetic nephropathy, and studies in mice with tissue-specific deletion of Adora2b in tubular epithelia or vascular endothelia implicated endothelial Adora2b signaling in protection from diabetic nephropathy. Finally, treatment with a selective Adora2b agonist (BAY 60-6583) conveyed potent protection from diabetes-associated kidney disease. Taken together, these findings implicate CD73-dependent production of extracellular adenosine and endothelial Adora2b signaling in kidney protection during diabetic nephropathy.

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Signaling through the A2B Adenosine Receptor Dampens Endotoxin-Induced Acute Lung Injury

Cited by 162 publications

References 55 publications

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

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

Netrin-1 Signaling Dampens Inflammatory Peritonitis

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

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Signaling through the A2B Adenosine Receptor Dampens Endotoxin-Induced Acute Lung Injury

Cited by 162 publications

References 55 publications

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

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

Netrin-1 Signaling Dampens Inflammatory Peritonitis

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

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

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