Role for L-selectin in lipopolysaccharide-induced activation of neutrophils

The activation of leucocytes by bacterial cell wall lipopolysaccharide (LPS) contributes to the pathogenesis of septic shock. LPS is known to interact with several cell-surface proteins, including CD14, when presented as a complex with serum LPS-binding protein. However, the identity of the receptor responsible for LPS signalling and leucocyte activation is unknown. Interestingly, mice deficient in cell-surface L-selectin were dramatically resistant to the lethal effects of high doses of LPS in a model of septic shock. Recently we reported that L-selectin binds to cardiolipin and other charged phospholipids at a site distinct from the carbohydrate-binding site. Structural similarities between charged phospholipids and the lipid A moiety of LPS prompted us to investigate interactions between L-selectin and LPS. Herein we show that L-selectin is a neutrophil surface receptor for LPS and lipotechoic acid. The binding of LPS to L-selectin is independent of serum and Ca2+, and is blocked by antibodies to L-selectin and fucoidan. Furthermore, the interaction of LPS with cell-surface L-selectin results in superoxide production, indicating that L-selectin can mediate both binding and activation of human neutrophils. These findings suggest novel therapeutic approaches for the treatment of septic shock.