L-selectin shedding affects bacterial clearance in the lung: a new regulatory pathway for integrin outside-in signaling

Abstract

Pneumonia induced by Gram-negative bacteria is a common and serious disease associated with high morbidity and mortality. Elimination of bacterial pathogens relies on the recruitment and functions of neutrophils. The adhesion molecule L-selectin has recently been implicated in integrin activation in neutrophils (inside-out signaling). However, the molecular mechanism by which L-selectin participates in host defense against Klebsiella pneumoniae-induced pulmonary inflammation is unknown. We demonstrate that L-selectin-deficient mice are prone to pulmonary infection compared with wild-type controls. Mechanistically, L-selectin cleavage from the neutrophil surface triggered by integrin engagement is involved in neutrophil recruitment into the lung and bacterial clearance. Downstream of integrin ligation, the metalloproteinase A disintegrin and metalloproteinase 17 (ADAM17) sheds L-selectin from the neutrophil surface in an IRhom2-dependent manner. L-selectin cleavage enhances integrin-mediated outside-in signaling, resulting in increased neutrophil effector functions. Thus, we identify a novel regulatory mechanism in neutrophils required for an adequate immune response triggered by integrin engagement during K pneumoniae-induced pulmonary inflammation.