CD39 and CD73 in immunity and inflammation

Antonioli, Luca; Pacher, Pál; Vizi, E.S.; Haskó, György

doi:10.1016/j.molmed.2013.03.005

Cited by 1,007 publications

(1,009 citation statements)

References 172 publications

(204 reference statements)

Supporting

Mentioning

966

Contrasting

Unclassified

Order By: Relevance

“…Transgenic mice with CD73 knockout have increased susceptibility to MI/R injury because of capillary dysfunction and innate immune cell extravasation 54. Upon treatment with adenosine‐receptor agonist or soluble CD73, these transgenic mice exhibit similar response to injury compared with wild‐type controls 54.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…These results suggest that the attenuated chemotactic activity of Irf8 −/− microglia in response to ATP is not merely due to the loss of purinoceptors. Extracellular ATP is hydrolyzed by ENTPDases (e.g., ENTPdase1, which is the dominant subtype in microglia [24]) to ADP and adenosine monophosphate (AMP) [14]. ADP activates P2Y 12 Rs, which is crucial for ATP-induced microglial chemotaxis [13].…”

Section: Irf8 Regulates the Expression Of Nucleotide-degrading Enzymesmentioning

confidence: 99%

“…However, the addition of a soluble ectonucleotidase restores the ability of ATP to be a chemoattractant [13]. AMP is further hydrolyzed by NT5e to adenosine [14], resulting in the activation of microglial A3Rs and subsequently further enhancing ATP-induced microglial chemotaxis [11]. Therefore, the balance of the expression of these enzymes may be critical for exhibiting chemotactic responses properly.…”

Section: Irf8 Regulates the Expression Of Nucleotide-degrading Enzymesmentioning

confidence: 99%

“…In addition, in vitro studies have shown that ionotropic P2X4 receptors (P2X4Rs) and adenosine A 3 receptors (A3Rs) are involved in ATP-induced chemotaxis of microglia [11,12]. Adenosine is released from cells or generated from extracellular ATP by ectonucleoside triphosphate diphosphohydrolases (ENTPDases) and ecto-5′-nucleotidase enzymes (NT5e; also known as CD73), both of which are expressed on the cell surface [13,14]. Therefore, the expression pattern of these purine receptors and even ATP-degrading enzymes may be a critical component for the ability of microglial motility.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

IRF8 is a transcriptional determinant for microglial motility

Masuda

Nishimoto

Tomiyama

et al. 2014

Purinergic Signalling

View full text Add to dashboard Cite

Microglia, the resident immune cells of the central nervous system, are constitutively mobile cells that undergo rapid directional movement toward sites of tissue disruption. However, transcriptional regulatory mechanisms of microglial motility remain unknown. In the present study, we show that interferon regulatory factor-8 (IRF8) regulates microglial motility. We found that ATP and complement component, C5a, induced chemotaxis of IRF8 wild-type microglia. However, these responses were markedly suppressed in microglia lacking IRF8 (Irf8 −/− ). In a consistent manner, phosphorylation of Akt (which plays a crucial role in ATP-induced chemotaxis) was abolished in Irf8 −/− microglia. Real-time polymerase chain reaction analysis revealed that motility-related microglial genes such as P2Y 12 receptor were significantly suppressed in Irf8 −/− microglia. Furthermore, Irf8 −/− microglia exhibited a differential expression pattern of nucleotidedegrading enzymes compared with their wild-type counterparts. Overall, our findings suggest that IRF8 may regulate microglial motility via the control of microglial gene expression.

show abstract

“…Cell‐surface ectonucleotidases (NTPDases) such as NTPDase1 (i.e. CD39), together with the ecto‐5′‐nucleotidase CD73, hydrolyze eATP to adenosine, a purine nucleoside with anti‐inflammatory effects 3, 6, 7. NTPDase1 is present at high levels in intestinal tissues from patients with IBD 8.…”

Section: Introductionmentioning

confidence: 99%

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

et al. 2018

View full text Add to dashboard Cite

Inflammatory bowel disease (IBD) is a condition of chronic inflammatory intestinal disorder with increasing prevalence but limited effective therapies. The purine metabolic pathway is involved in various inflammatory processes including IBD. However, the mechanisms through which purine metabolism modulates IBD remain to be established. Here, we found that mucosal expression of genes involved in the purine metabolic pathway is altered in patients with active ulcerative colitis (UC), which is associated with elevated gene expression signatures of the group 3 innate lymphoid cell (ILC3)–interleukin (IL)‐22 pathway. In mice, blockade of ectonucleotidases (NTPDases), critical enzymes for purine metabolism by hydrolysis of extracellular adenosine 5′‐triphosphate (eATP) into adenosine, exacerbates dextran‐sulfate sodium‐induced intestinal injury. This exacerbation of colitis is associated with reduction of colonic IL‐22‐producing ILC3s, which afford essential protection against intestinal inflammation, and is rescued by exogenous IL‐22. Mechanistically, activation of ILC3s for IL‐22 production is reciprocally mediated by eATP and adenosine. These findings reveal that the NTPDase‐mediated balance between eATP and adenosine regulates ILC3 cell function to provide protection against intestinal injury and suggest potential therapeutic strategies for treating IBD by targeting the purine–ILC3 axis.

show abstract

CD39 and CD73 in immunity and inflammation

Cited by 1,007 publications

References 172 publications

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

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

IRF8 is a transcriptional determinant for microglial motility

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

Contact Info

Product

Resources

About