A2A adenosine receptors and C/EBPβ are crucially required for IL-10 production by macrophages exposed to Escherichia coli

Csóka, Balázs; Németh, Zoltán; Virág, László; Gergely, Pál; Leibovich, Samuel; Pacher, Pál; Sun, Chenxing; Blackburn, Michael R.; Vizi, E.S.; Deitch, Edwin A.; Haskó, György

doi:10.1182/blood-2007-01-065870

Cited by 179 publications

(147 citation statements)

References 71 publications

Supporting

Mentioning

136

Contrasting

Order By: Relevance

“…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 For personal use only. on May 12, 2018. by guest www.bloodjournal.org From coupled receptors associated with the Gas subunit and are capable of activating adenylate cyclase and enhancing intracellular cyclic AMP (cAMP) levels.…”

Section: Discussionmentioning

confidence: 99%

“…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. 44 We previously demonstrated that stimulating macrophages in the presence of cAMP led to the development of the regulatory phenotype 25 and the activation of G-protein coupled receptors resulted in extracellular signal-regulated kinase (ERK)-dependent IL-10 hyperinduction.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Cohen

Briggs

Marino

et al. 2013

Blood

123

139

View full text Add to dashboard Cite

• 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 ...

show abstract

Section: Discussionmentioning

confidence: 99%

“…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. 44 We previously demonstrated that stimulating macrophages in the presence of cAMP led to the development of the regulatory phenotype 25 and the activation of G-protein coupled receptors resulted in extracellular signal-regulated kinase (ERK)-dependent IL-10 hyperinduction.…”

Section: Discussionmentioning

confidence: 99%

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

Cohen

Briggs

Marino

et al. 2013

Blood

123

139

View full text Add to dashboard Cite

show abstract

“…A 2B AR-KO mice on a C57BL/6 background were described in a previous report (13). All mice were maintained in pathogenfree condition with standard laboratory chow and water ad libitum.…”

Section: Micementioning

confidence: 99%

Blocking A2B Adenosine Receptor Alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and Th17 Differentiation

Wei

et al. 2013

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Adenosine is a key endogenous signaling molecule that regulates immune responses. A2B adenosine receptor (AR) is a relatively low-affinity receptor for adenosine, and the activation of A2BAR is believed to require pathological level of adenosine that is associated with ischemia, inflammation, trauma, or other types of stress. The role of A2BAR in the pathogenesis of multiple sclerosis (MS) is still unclear. In this study, we discovered that A2BAR was upregulated both in the peripheral blood leukocytes of MS patients and the peripheral lymphoid tissues of experimental autoimmune encephalomyelitis (EAE) mice. A2BAR-specific antagonists, CVT-6883 and MRS-1754, alleviated the clinical symptoms of EAE and protected the CNS from immune damage. A2BAR-knockout mice also developed less severe EAE. Further study indicated that blocking or deleting A2BAR inhibited Th17 cell differentiation by blocking IL-6 production from APCs such as dendritic cells. In dendritic cells, A2BAR was also upregulated during the development of EAE. CVT-6883 and genetic deletion of A2BAR significantly reduced adenosine-mediated IL-6 production. The phospholipase Cβ–protein kinase C and p38 MAPK pathways were found to be involved in the A2BAR-mediated IL-6 production. Our findings not only revealed the pathological role of A2BAR in EAE, but also suggested that this receptor might be a new therapeutic target for the development of anti-MS drugs.

show abstract

“…A 2B KO mice were obtained from Deltagen (San Mateo, CA), and WT C57BL/6 mice were purchased from Harlan World Headquarters (Indianapolis, IN). Genotyping protocols for A 2B KO have been previously described (23). All of the A 2B KO mice used in these studies were back-crossed to the C57BL/6 genetic background for more than 10 generations.…”

Section: Animalsmentioning

confidence: 99%

Attenuation of Chronic Pulmonary Inflammation in A_2B Adenosine Receptor Knockout Mice

Zaynagetdinov

Ryzhov

Goldstein

et al. 2010

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Pharmacologic evidence suggests that activation of A 2B adenosine receptors results in proinflammatory effects relevant to the progression of asthma, a chronic lung disease associated with elevated interstitial adenosine concentrations in the lung. This concept has been challenged by the finding that genetic removal of A 2B receptors leads to exaggerated responses in models of acute inflammation. Therefore, the goal of our study was to determine the effects of A 2B receptor gene ablation in the context of ovalbumin-induced chronic pulmonary inflammation. We found that repetitive airway allergen challenge induced a significant increase in adenosine levels in fluid recovered by bronchoalveolar lavage. Genetic ablation of A 2B receptors significantly attenuated allergen-induced chronic pulmonary inflammation, as evidenced by a reduction in the number of bronchoalveolar lavage eosinophils and in peribronchial eosinophilic infiltration. The most striking difference in the pulmonary inflammation induced in A 2B receptor knockout (A 2B KO) and wildtype mice was the lack of allergen-induced IL-4 release in the airways of A 2B KO animals, in line with a significant reduction in IL-4 protein and mRNA levels in lung tissue. In addition, attenuation of allergeninduced transforming growth factor-b release in airways of A 2B KO mice correlated with reduced airway smooth muscle and goblet cell hyperplasia/hypertrophy. In conclusion, genetic removal of A 2B adenosine receptors in mice leads to inhibition of allergen-induced chronic pulmonary inflammation and airway remodeling. These findings are in agreement with previous pharmacologic studies suggesting a deleterious role for A 2B receptor signaling in chronic lung inflammation.Keywords: adenosine; asthma; pulmonary inflammation; IL-4; transforming growth factor-bInterstitial adenosine concentrations are increased during inflammation as a result of cell stress, injury, and tissue hypoxia (1, 2). Extracellular adenosine functions as a signaling molecule by engaging cell surface G protein-coupled receptors of the P1 purinergic family comprising A 1 , A 2A , A 2B , and A 3 adenosine receptor subtypes (2). There is growing evidence that adenosine plays an important role in the regulation of inflammation. Inhibition of acute inflammation is a well-recognized effect of adenosine, which has been attributed primarily to stimulation of A 2A adenosine receptors on immune and endothelial cells (3). Recent evidence, however, suggests that adenosine can promote chronic inflammation by up-regulating proinflammatory cytokines. Studies in adenosine deaminase (ADA)-deficient mice, characterized by elevated lung tissue levels of adenosine, demonstrated an association between adenosine and an inflammatory phenotype (4, 5). These mice exhibit a pulmonary phenotype with features of inflammation, mucous metaplasia, increased IgE synthesis, and elevated levels of proinflammatory cytokines, all of which could be reversed by lowering adenosine levels with exogenous ADA (4). Correlation between lung ad...

show abstract

A2A adenosine receptors and C/EBPβ are crucially required for IL-10 production by macrophages exposed to Escherichia coli

Cited by 179 publications

References 71 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

Blocking A2B Adenosine Receptor Alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and Th17 Differentiation

Attenuation of Chronic Pulmonary Inflammation in A_2B Adenosine Receptor Knockout Mice

Contact Info

Product

Resources

About

A2A adenosine receptors and C/EBPβ are crucially required for IL-10 production by macrophages exposed to Escherichia coli

Cited by 179 publications

References 71 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

Blocking A2B Adenosine Receptor Alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and Th17 Differentiation

Attenuation of Chronic Pulmonary Inflammation in A2B Adenosine Receptor Knockout Mice

Contact Info

Product

Resources

About

Attenuation of Chronic Pulmonary Inflammation in A_2B Adenosine Receptor Knockout Mice