Modulation of myeloid cells by adenosine signaling

Cekic, Caglar

doi:10.1016/j.coph.2020.08.012

Cited by 5 publications

(5 citation statements)

References 117 publications

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“…Similar effects have been reported in other organs, such as liver and kidney [120,121]. Additionally, adenosine directly regulates cells of the immune system, such as myeloid cells [122].…”

Section: The Molecular Role Of Tnap In Inflammation Processessupporting

confidence: 69%

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

Graser

Liedtke

Jakob

2021

IJMS

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This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here.

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“…Similar effects have been reported in other organs, such as liver and kidney [120,121]. Additionally, adenosine directly regulates cells of the immune system, such as myeloid cells [122].…”

Section: The Molecular Role Of Tnap In Inflammation Processessupporting

confidence: 69%

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

Graser

Liedtke

Jakob

2021

IJMS

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“…Indeed, consistent with this, we observed that activation of cDC2s in vitro with poly IC led to a significant increase in A 2A R expression and in vivo, treatment with immune checkpoint blockade, particularly anti-CTLA-4, led to a significant increase in A 2A R expression on cDC2s. Expression of A 2A R and A 2B R on dendritic cells has been reported previously 50 and blockade of A 2B R or CD73 9 , 51 or myeloid-specific deletion of A 2A R or A 2B R has been shown to enhance anti-tumor immunity 27 , 52 in part through modulation of DC function 53 . More recently, it was shown that a component of the mechanism of action for the small molecule A 2A R antagonist AZD4635 was enhancement of cDC1 function 54 .…”

Section: Discussionmentioning

confidence: 76%

A2AR eGFP reporter mouse enables elucidation of A2AR expression dynamics during anti-tumor immune responses

Todd,

Lai,

Sek

et al. 2023

Nat Commun

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There is significant clinical interest in targeting adenosine-mediated immunosuppression, with several small molecule inhibitors having been developed for targeting the A2AR receptor. Understanding of the mechanism by which A2AR is regulated has been hindered by difficulty in identifying the cell types that express A2AR due to a lack of robust antibodies for these receptors. To overcome this limitation, here an A2AR eGFP reporter mouse is developed, enabling the expression of A2AR during ongoing anti-tumor immune responses to be assessed. This reveals that A2AR is highly expressed on all tumor-infiltrating lymphocyte subsets including Natural Killer (NK) cells, NKT cells, γδ T cells, conventional CD4+ and CD8+ T lymphocytes and on a MHCIIhiCD86hi subset of type 2 conventional dendritic cells. In response to PD-L1 blockade, the emergence of PD-1+A2AR- cells correlates with successful therapeutic responses, whilst IL-18 is identified as a cytokine that potently upregulates A2AR and synergizes with A2AR deficiency to improve anti-tumor immunity. These studies provide insight into the biology of A2AR in the context of anti-tumor immunity and reveals potential combination immunotherapy approaches.

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“…Such genes included fosb , fosl , nr4a1 , and nr4a2, which contribute to A2aR-induced immunosuppression. A2aR acts through cAMP signaling and PKA to inhibit NF-κB via NR4a and the FOS family proteins ( 24 – 26 ) ( Fig. 2B ).…”

Section: Resultsmentioning

confidence: 99%

Staphylococcus aureus suppresses the pentose phosphate pathway in human neutrophils via the adenosine receptor A2aR to enhance intracellular survival

Vozza,

Daly,

O'Rourke

et al. 2024

mBio

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Staphylococcus aureus propensity for intracellular survival presents a challenge to effectively treat infection, with significant evidence suggesting S. aureus can hijack phagocytes for host dissemination, worsening clinical outcomes. Human polymorphonuclear neutrophils (hPMN) have been identified as an important conduit for the intracellular survival of S. aureus, yet this immune evasion mechanism remains incompletely understood. Multiplex gene expression analysis was used to profile the gene expression of hPMN harboring intracellular S. aureus and found that the anti-inflammatory adenosine receptor, adora2a (A2aR), was upregulated along with several A2aR- associated genes. Importantly, treatment with the A2aR inhibitor, ZM-241385, reduced intracellular survival of S. aureus within hPMN while enhancing ROS production and neutrophil extracellular traps. This suggests that S. aureus uses A2aR to dampen hPMN effector functions as a mechanism to boost intracellular survival. A2aR inhibition led to a metabolic switch from glycolysis to the pentose phosphate pathway (PPP) in hPMN, which facilitated an increase in NADPH levels and reactive oxygen species (ROS) production. Taken together, our work highlights the importance of the A2aR, which is targeted by S. aureus to suppress the PPP, limiting ROS production, and thus creating a more hospitable intracellular niche in which to survive. IMPORTANCE Staphylococcus aureus is one of the leading causes of antimicrobial-resistant infections whose success as a pathogen is facilitated by its massive array of immune evasion tactics, including intracellular survival within critical immune cells such as neutrophils, the immune system’s first line of defense. In this study, we describe a novel pathway by which intracellular S. aureus can suppress the antimicrobial capabilities of human neutrophils by using the anti-inflammatory adenosine receptor, adora2a (A2aR). We show that signaling through A2aR suppresses the pentose phosphate pathway, a metabolic pathway used to fuel the antimicrobial NADPH oxidase complex that generates reactive oxygen species (ROS). As such, neutrophils show enhanced ROS production and reduced intracellular S. aureus when treated with an A2aR inhibitor. Taken together, we identify A2aR as a potential therapeutic target for combatting intracellular S. aureus infection.

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Modulation of myeloid cells by adenosine signaling

Cited by 5 publications

References 117 publications

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

A2AR eGFP reporter mouse enables elucidation of A2AR expression dynamics during anti-tumor immune responses

Staphylococcus aureus suppresses the pentose phosphate pathway in human neutrophils via the adenosine receptor A2aR to enhance intracellular survival

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