Adenosine: An endogenous modulator of innate immune system with therapeutic potential

Kumar, Vijay; Sharma, Ambika

doi:10.1016/j.ejphar.2009.05.005

Cited by 162 publications

(113 citation statements)

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“…Extracellular adenosine and adenine nucleotides control a variety of cell function. [16][17][18] Microscopic analysis showed that, in contrast to 3 0 -deoxyadenosine, ATP, ADP and adenosine did not inhibit thapsigargin-induced cell injury (Figure 2a). Quantitative analysis confirmed that ER stress-induced cellular death was not affected by the treatment with these adenosine-related substances (Figure 2b).…”

Section: Resultsmentioning

confidence: 99%

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

et al. 2011

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The unfolded protein response (UPR) is involved in a diverse range of pathologies triggered by endoplasmic reticulum (ER) stress. Endeavor to seek selective regulators of the UPR is a promising challenge towards therapeutic intervention in ER stressrelated disorders. In the present report, we describe aberrant, differential and bidirectional regulation of the UPR by 3 0 -deoxyadenosine (cordycepin) towards cell survival. 3 0 -Deoxyadenosine blocked ER stress-induced apoptosis via inhibiting the IRE1-JNK pro-apoptotic pathway. 3 0 -Deoxyadenosine also inhibited apoptosis through reinforcement of the pro-survival eIF2a signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2a, and dephosphorylation of eIF2a by salubrinal mimicked the anti-apoptotic effect of 3 0 -deoxyadenosine. Unexpectedly, although 3 0 -deoxyadenosine caused activation of eIF2a, it inhibited downstream pro-apoptotic events including induction of ATF4 and expression of CHOP. Cooperation of adenosine transporter and A3 adenosine receptor, but not A1/A2 receptors, mediated the pluripotent effects of 3 0 -deoxyadenosine. In mice, ER stress caused activation of JNK, expression of CHOP and induction of apoptosis in renal tubules. The apoptosis was significantly attenuated by administration with 3 0 -deoxyadenosine, and it was correlated with blunted induction of JNK and CHOP in the kidney. These results disclosed atypical pro-survival regulation of the UPR by 3 0 -deoxyadenosine, which may be advantageous for the treatment of intractable, ER stress-related disorders. Endoplasmic reticulum (ER) stress-mediated tissue injury is implicated in a wide range of pathologies including cancers, infection, atherosclerosis, ischemia, neurodegenerative disorders and metabolic diseases such as diabetes mellitus.

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Section: Resultsmentioning

confidence: 99%

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

et al. 2011

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“…The presence of adenosine in the extracellular environment may facilitate the persistence of Leishmania in the host due to its immunosuppressive properties [9,12,13,20,21]. A recent study showed that CD39 expression and adenosine production were increased in a population of tolerogenic DCs, which were characterised by low levels of CD40 expression and IL-12p40 production and a decreased ability to induce T-cell proliferation [42].…”

Section: Discussionmentioning

confidence: 99%

“…Extracellular ATP, which is accumulated following cellular injury, has important inflammatory properties characterised by the induction of IL-12 and TNF-α production [8][9][10][11]. On the other hand, adenosine has been recognised as an immunomodulatory molecule that inhibits the release of proinflammatory cytokines and induces the release of IL-10 [9,12,13]. The combined action of CD39, which sequentially hydrolyses ATP to ADP and then to AMP, and CD73, which converts AMP to adenosine is essential in controlling extracellular levels of ATP [9].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, activation of A 2B receptors also induces ERK1/2 phosphorylation [34,41]. Thus, the blockade of A 2B receptors in L. amazonensis-infected DCs may have led to inhibition of ERK1/2 phosphorylation with subsequent restoration of CD40 expression.The presence of adenosine in the extracellular environment may facilitate the persistence of Leishmania in the host due to its immunosuppressive properties [9,12,13,20,21]. A recent study showed that CD39 expression and adenosine production were increased in a population of tolerogenic DCs, which were characterised by low levels of CD40 expression and IL-12p40 production and a decreased ability to induce T-cell proliferation [42].…”

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Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A_2B adenosine receptor activation

et al. 2012

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Dendritic cells (DCs) play an essential role in the modulation of immune responses and several studies have evaluated the interactions between Leishmania parasites and DCs.While extracellular ATP exhibits proinflammatory properties, adenosine is an important anti-inflammatory mediator. Here we investigated the effects of Leishmania infection on DC responses and the participation of purinergic signalling in this process. Bone marrowderived dendritic cells (BMDCs) from C57BL/6J mice infected with Leishmania amazonensis, Leishmania braziliensis or Leishmania major metacyclic promastigotes showed decreased major histocompatibility complex (MHC) class II and CD86 expression and increased ectonucleotidase expression as compared with uninfected cells. In addition, L. amazonensis-infected DCs, which had lower CD40 expression, exhibited a decreased ability to induce T-cell proliferation. The presence of MRS1754, a highly selective A 2B adenosine receptor antagonist at the time of infection increased MHC class II, CD86 and CD40 expression in L. amazonensis-infected DCs and restored the ability of the infected DCs to induce T-cell proliferation. Similar results were obtained through the inhibition of extracellular ATP hydrolysis using suramin. In conclusion, we propose that A 2B receptor activation may be used by L. amazonensis to inhibit DC function and evade the immune response. Keywords: Adenosine receptors r CD40 r Dendritic cell r Ectonucleotidases r Leishmania amazonensis IntroductionLeishmaniasis is a group of diseases that are caused by obligate intracellular parasites of the genus Leishmania. Leishmania infections can result in a wide spectrum of clinical manifestations and disease outcome is determined both by the parasite species and by Correspondence: Dr. Luís C. C. Afonso e-mail: afonso@nupeb.ufop.br the host immune response. Leishmania amazonensis differs from other species because it is able to cause chronic non-healing lesions in mouse strains genuinely resistant to other Leishmania species, such as Leishmania braziliensis and Leishmania major [1][2][3]. In humans, L. amazonensis causes diffuse cutaneous leishmaniasis, a condition characterised by a lack of antigen-specific T-cell responses against the parasite [4].DCs play a critical role in orchestrating the innate and adaptive components of the immune system [5,6]. Immature DCs capture and process antigens located throughout the body. After contacting microorganisms or other inflammatory substances, C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu1204 Amanda B. Figueiredo et al. Eur. J. Immunol. 2012. 42: 1203-1215 these cells initiate their maturation process. DC maturation is characterised by increased expression of major histocompatibility complex (MHC) class II (MHCII) and co-stimulatory molecules, such as CD40, CD80, CD86 and CD54; decreased phagocytic capacity; increased cytokine secretion and expression of different chemokine receptors [5,7]. Extracellular ATP, which is accumulated following cellular injury, has important inf...

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“…While better recognized for its extensive role in the regulation of vascular tone,16 adenosine also acts through adenosine receptors on immune cells to exert counter‐regulatory signals that inhibit chemotaxis, leukocyte adhesion, and reactive oxygen species (ROS) formation. Additionally, adenosine signaling can promote angiogenic activity, anti‐inflammatory cytokine secretion, and leukocytic efferocytosis of apoptotic cells in a manner that is protective of the heart during MI/R 17, 18, 19, 20, 21…”

Section: Introductionmentioning

confidence: 99%

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

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BackgroundDuring myocardial ischemia/reperfusion (MI/R) injury, there is extensive release of immunogenic metabolites that activate cells of the innate immune system. These include ATP and AMP, which upregulate chemotaxis, migration, and effector function of early infiltrating inflammatory cells. These cells subsequently drive further tissue devitalization. Mesenchymal stromal cells (MSCs) are a potential treatment modality for MI/R because of their powerful anti‐inflammatory capabilities; however, the manner in which they regulate the acute inflammatory milieu requires further elucidation. CD73, an ecto‐5′‐nucleotidase, may be critical in regulating inflammation by converting pro‐inflammatory AMP to anti‐inflammatory adenosine. We hypothesized that MSC‐mediated conversion of AMP into adenosine reduces inflammation in early MI/R, favoring a micro‐environment that attenuates excessive innate immune cell activation and facilitates earlier cardiac recovery.Methods and ResultsAdult rats were subjected to 30 minutes of MI/R injury. MSCs were encapsulated within a hydrogel vehicle and implanted onto the myocardium. A subset of MSCs were pretreated with the CD73 inhibitor, α,β‐methylene adenosine diphosphate, before implantation. Using liquid chromatography/mass spectrometry, we found that MSCs increase myocardial adenosine availability following injury via CD73 activity. MSCs also reduce innate immune cell infiltration as measured by flow cytometry, and hydrogen peroxide formation as measured by Amplex Red assay. These effects were dependent on MSC‐mediated CD73 activity. Finally, through echocardiography we found that CD73 activity on MSCs was critical to optimal protection of cardiac function following MI/R injury.Conclusions MSC‐mediated conversion of AMP to adenosine by CD73 exerts a powerful anti‐inflammatory effect critical for cardiac recovery following MI/R injury.

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Adenosine: An endogenous modulator of innate immune system with therapeutic potential

Cited by 162 publications

References 114 publications

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A_2B adenosine receptor activation

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

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Adenosine: An endogenous modulator of innate immune system with therapeutic potential

Cited by 162 publications

References 114 publications

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine

Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A2B adenosine receptor activation

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

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Leishmania amazonensis impairs DC function by inhibiting CD40 expression via A_2B adenosine receptor activation