Abstract
Rapid neutrophil recruitment is critical for the efficient clearance of bacterial pathogens from the lungs. Although β(2) integrins and their activation are required for neutrophil recruitment from postcapillary venules of the systemic circulation into inflamed tissues, the involvement of integrins in neutrophil recruitment in response to respiratory infection varies among bacterial pathogens. For stimuli eliciting β(2) integrin-dependent neutrophil influx, including Pseudomonas aeruginosa, it remains unclear whether the activation of β(2) integrins is an essential step in this process. In the current study, we analyze neutrophil trafficking within the lungs of mice infected with Pseudomonas aeruginosa and evaluate the role of β(2) integrin activation through genetic deletion of talin-1 or Kindlin-3 or by pharmacological inhibition of high-affinity β(2) integrins using a small molecule allosteric antagonist. We observe that attenuation of high-affinity β(2) integrins leads to an enhancement of neutrophil emigration into lung interstitium and airspaces. Neutrophil effector functions, including the production of reactive oxygen species and the phagocytosis of bacteria, are only partially dependent on high-affinity β(2) integrins. These results reveal a mechanism by which activated β(2) integrins limit neutrophil entry into the lung tissue and airspaces during acute pseudomonal pneumonia and suggest potential strategies for modulating neutrophil-mediated host defense.