Rationale:
During myocardial ischemia/reperfusion (MI/R) injury there is excessive release of immunogenic metabolites that activate cells of the innate immune system. These metabolites include adenine nucleotides such as adenosine triphosphate (ATP) and adenosine monophosphate (AMP) which up-regulate 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 due to their powerful anti-inflammatory capabilities; however, the manner in which they regulate the acute inflammatory milieu requires further elucidation. Surface membrane ecto-5’-nucleotidase CD73 may play a critical role in inflammatory regulation by converting pro-inflammatory AMP to anti-inflammatory adenosine (ADO). We hypothesized that the MSC-mediated conversion of AMP into ADO reduces inflammation in early MI/R, favoring a micro-environment that attenuates excessive innate immune cell activation and facilitates earlier cardiac recovery.
Objective:
To determine the contribution of MSC-mediated production of ADO in regulating the innate inflammatory response following MI/R.
Methods and Results:
Adult 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 treated with the CD73 inhibitor, α,β-methylene adenosine diphosphate, prior to implantation. Using liquid chromatography/mass spectrometry, we found MSCs increase myocardial ADO availability following injury via CD73 activity. We also demonstrated that MSCs reduce innate immune cell infiltration as measured by flow cytometry and hydrogen peroxide formation as measured by Amplex Red assay. These effects were also dependent on MSC-mediated CD73 activity. Furthermore, through echocardiography we found CD73 activity on MSCs was critical to optimal protection of cardiac function following MI/R injury.
Conclusion:
MSC-mediated conversion of AMP to ADO by CD73 ecto-5’-nucleotidase activity exerts a powerful anti-inflammatory effect following MI/R injury.
Particulate and solubilized β-glucan and non-β-glucan fractions of Euglena gracilis induce pro- and anti-inflammatory innate immune cell responses and exhibit antioxidant properties
