Rationale: Activation of the adenosine A_2B receptor (A_2BR) promotes antiinflammatory effects in diverse biological settings, but the role of this receptor in antimicrobial host defense in the lung has not been established. Gram-negative bacillary pneumonia is a common and serious illness associated with high morbidity and mortality, the treatment of which is complicated by increasing rates of antibiotic resistance.

Objectives: To test the hypothesis that absence of adenosine A_2B receptor signaling promotes host defense against bacterial pneumonia.

Methods: We used a model of Klebsiella pneumoniae pneumonia in wild-type mice and mice with targeted deletion of the A_2BR. Host responses were compared in vivo and leukocyte responses to the bacteria were examined in vitro.

Measurements and Main Results: A_2BR^–/– mice demonstrated enhanced bacterial clearance from the lung and improved survival after infection with K. pneumoniae compared with wild-type controls, an effect that was mediated by bone marrow–derived cells. Leukocyte recruitment to the lungs and expression of inflammatory cytokines did not differ between A_2BR^–/– and wild-type mice, but A_2BR^–/– neutrophils exhibited sixfold greater bactericidal activity and enhanced production of neutrophil extracellular traps compared with wild-type neutrophils when incubated with K. pneumoniae. Consistent with this finding, bronchoalveolar lavage fluid from A_2BR^–/– mice with Klebsiella pneumonia contained more extracellular DNA compared with wild-type mice with pneumonia.

Conclusions: These data suggest that the absence of A_2BR signaling enhances antimicrobial activity in gram-negative bacterial pneumonia.