Extracellular adenosine released by mesenchymal stromal cells from young hosts boosts the antimicrobial activity of neutrophils from aged hosts against Streptococcus pneumoniae

Mesenchymal stem cells (MSC) represent a potential target to reverse inflammaging and to halt immunosenescence, as these cells can modulate immune cell responses. Neutrophils, known as polymorphonuclear leukocytes (PMNs), are required for host defence against bacterial pathogens such as Streptococcus pneumoniae; however, their function significantly declines with age. Whether MSCs can reverse the age-driven decline in PMN antibacterial function is unknown. To test that, we cultured MSCs from young and aged mice and tested the paracrine effect of factors present in the conditioned media (CM) on antimicrobial responses of PMNs across host age. The ex vivo treatment with MSCs-CM from aged mice blunted the antimicrobial activity of PMNs from young hosts. However, treatment of PMNs from aged mice with young MSCs-CM significantly increased S. pneumoniae uptake, production of mitochondrial reactive oxygen species, and boosted overall bacterial killing. In exploring the pathways involved, we found that presence of immune modulatory extracellular adenosine in the young MSCs-CM was required for boosting PMN responses. Further, in contrast to aged mice MSCs-CM, young mice MSCs CM increased the responsiveness of aged mice PMNs to adenosine activation by upregulating the A1 adenosine receptor expression. Blocking this high affinity adenosine receptor reversed the rejuvenating effect of young mice MSCs-CM on bacterial killing by PMNs from aged hosts. In summary, this study suggests a potential cell-free therapeutic role of the young host MSC secretome in reversing the age-driven defects in PMN function against bacterial infection. It is the first study to demonstrate an anti-immunosenescence activity of the MSC secretome through extracellular adenosine.