Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction

Yan, Xiaoxiang; Anzai, Atsushi; Katsumata, Yoshinori; Matsuhashi, Tomohiro; Ito, Kaname; Endo, Jin; Yamamoto, Tsunehisa; Takeshima, Akiko; Shinmura, Ken; Shi, Weifeng; Fukuda, Keiichi; Sano, Motoaki

doi:10.1016/j.yjmcc.2013.04.023

Cited by 492 publications

(485 citation statements)

References 36 publications

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“…They are responsible for amplifying pro‐inflammatory cytokines, generating ROS, and exacerbating cardiac dysfunction 10, 30, 48. We used flow cytometry to determine the number of immune cells within the LV tissue 1 and 3 days after MI/R.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…Rats were subjected to MI/R injury by transient ligation of the left anterior descending artery or to sham operation with ligation as previously described 29, 30, 31. Rats were anesthetized with 2.0% isoflurane gas (Diamondback Drugs, Scottsdale, AZ), intubated, and mechanically ventilated with a rodent respirator.…”

Section: Methodsmentioning

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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“…These immune processes participate in wound healing but may also be harmful to organ function, and proinflammatory cytokines are involved in the post-I/R sequence injuries (33,37,38). Although increasing evidence indicates that DCs likely play a key role during and after I/R (8,39,40), their specific role remains to be further explored. Some authors showed that DCs might be either protective (16) or detrimental (9, 41) for the reperfused myocardium.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

Chadet

Ivanès

Benoist

et al. 2015

The Journal of Immunology

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High concentrations of extracellular ATP (eATP) resulting from cell damage may be found during an ischemia/reperfusion (I/R) episode at the site of injury. eATP activates purinergic receptors in dendritic cells (DCs) and may inhibit inflammation. This immunosuppressive activity could be of interest in the field of I/R, which is an inflammatory condition involved in myocardial infarction, stroke, and solid organ transplantation. However, the specific purinergic receptor responsible for this effect remains to be identified. In this study, we report that eATP induced maturation of human monocyte-derived DCs. Additionally, eATP inhibited IL-12 production whereas IL-10 levels remained unchanged in activated DCs. These effects were prevented by the P2Y11R antagonist NF340. Interestingly, a 5-h hypoxia prevented the effects of eATP on cytokine production whereas a 1-h hypoxia did not affect the eATP-mediated decrease of IL-12 and IL-6. We showed a time-dependent downregulation of P2Y11R at both mRNA and protein levels that was prevented by knocking down hypoxia-inducible factor-1α. In this study, we showed an immunosuppressive role of P2Y11R in human DCs. Additionally, we demonstrated that the time-dependent downregulation of P2Y11R by hypoxia orientates DCs toward a proinflammatory phenotype that may be involved in post-I/R injuries as observed after organ transplantation.

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“…Moreover, the M2 subset can be also detrimental to the host, leading to tissue fibrosis when their matrix-enhancing activity is not regulated (6). Although Ma can be driven to either M1 or M2 phenotype, the complex in vivo cardiac environment typically produces intermediate phenotypes that coexpress both M1 and M2 markers (7,8). Nevertheless, some helminth parasite infections induce monocyte recruitment and subsequent expansion of cardiac Ma that become strongly M2-like cells (7), suggesting that myocardial Ma are able to be selectively skewed toward an M2-polarized phenotype in response to Th2-type immunological challenge.…”

Section: Hagas Disease Is Caused Bymentioning

confidence: 99%

CD73 Inhibition Shifts Cardiac Macrophage Polarization toward a Microbicidal Phenotype and Ameliorates the Outcome of Experimental Chagas Cardiomyopathy

Ponce

Sanmarco

Eberhardt

et al. 2016

The Journal of Immunology

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Increasing evidence demonstrates that generation of extracellular adenosine from ATP, which is hydrolyzed by the CD39/CD73 enzyme pair, attenuates the inflammatory response and deactivates macrophage antimicrobial mechanisms. Although CD73 is emerging as a critical pathway and therapeutic target in cardiovascular disorders, the involvement of this ectonucleotidase during myocardial infection has not been explored. Using a murine model of infection with Trypanosoma cruzi, the causal agent of Chagas cardiomyopathy, we observed a sudden switch from the classical M1 macrophage (microbicidal) phenotype toward an alternative M2 (repairing/anti-inflammatory) phenotype that occurred within the myocardium very shortly after BALB/c mice infection. The observed shift in M1/M2 rate correlated with the cardiac cytokine milieu. Considering that parasite persistence within myocardium is a necessary and sufficient condition for the development of the chronic myocarditis, we hypothesized that CD73 activity may counteract cardiac macrophage microbicidal polarization, rendering the local immune response less effective. In fact, a transient treatment with a specific CD73 inhibitor (adenosine 5′-α,β-methylene-diphosphate) enhanced the microbicidal M1 subset predominance, diminished IL-4– and IL-10–producing CD4+ T cells, promoted a proinflammatory cytokine milieu, and reduced parasite load within the myocardium during the acute phase. As a direct consequence of these events, there was a reduction in serum levels of creatine kinase muscle–brain isoenzyme, a myocardial-specific injury marker, and an improvement in the electrocardiographic characteristics during the chronic phase. Our results demonstrate that this purinergic system drives the myocardial immune response postinfection and harbors a promising potential as a therapeutic target.

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Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction

Cited by 492 publications

References 36 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

Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

CD73 Inhibition Shifts Cardiac Macrophage Polarization toward a Microbicidal Phenotype and Ameliorates the Outcome of Experimental Chagas Cardiomyopathy

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