Extracellular adenosine enhances the ability of PMNs to kill Streptococcus pneumoniae by inhibiting IL-10 production

Abstract

PMNs are crucial for initial control of Streptococcus pneumoniae (pneumococcus) lung infection; however, as the infection progresses their persistence in the lungs becomes detrimental. Here we explored why the anti-microbial efficacy of PMNs declines over the course of infection. We found that the progressive inability of PMNs to control infection correlated with phenotypic differences characterized by a decrease in CD73 expression, an enzyme required for production of extracellular adenosine (EAD). EAD production by CD73 was crucial for the ability of both murine and human PMNs to kill S. pneumoniae. In exploring the mechanisms by which CD73 controlled PMN function, we found that CD73 mediated its anti-microbial activity by inhibiting IL-10 production. PMNs from wild type mice did not increase IL-10 production in response to S. pneumoniae, however, CD73^-/- PMNs up-regulated IL-10 production upon pneumococcal infection in vitro and during lung challenge. IL-10 inhibited the ability of wild type PMNs to kill pneumococci. Conversely, blocking IL-10 boosted the bactericidal activity of CD73^-/- PMNs as well as host resistance of CD73^-/- mice to pneumococcal pneumonia. CD73/IL-10 did not affect apoptosis, bacterial uptake and intracellular killing or production of anti-microbial Neutrophil Elastase and Myeloperoxidase. Rather, inhibition of IL-10 production by CD73 was important for optimal ROS production by PMNs. ROS contributed to PMN anti-microbial function as their removal or detoxification impaired the ability of PMNs to efficiently kill S. pneumoniae. This study demonstrates that CD73 controls PMN anti-microbial phenotype during S. pneumoniae infection.