Plasma retinol binding protein 4 improves survival of Klebsiella pneumoniae-induced pneumosepsis through stimulation of neutrophils

A decrease in plasma retinol binding protein 4 (RBP4) was seen in sepsis patients. It is unknown whether the reduction is a specific indicator of sepsis or plays a role in sepsis pathogenesis. We addressed these questions using human cohorts consisting of 80 healthy, 68 non-sepsis infection (control for sepsis) and 471 sepsis subjects, and a mouse model of Klebsiella pneumoniae (KP)-induced pneumosepsis (KPS). Compared with healthy group, plasma RBP4 was markedly decreased in non-sepsis infection and sepsis patients. However, no difference was found between non-sepsis infection and sepsis groups. Lower RBP4 in sepsis patients was associated with increased mortality. In KPS mice, RBP4 knockout resulted in decreased survival. Intravenous administrations of recombinant RBP4 (rRBP4) improved the survival. The protective effect of RBP4 was selectively associated with augmented function of alveolar neutrophils. In vitro, both endogenous and exogenous RBP4 exhibited stimulatory effects on myeloperoxidase expression, KP phagocytosis and killing in neutrophils. Immunoprecipitations revealed a selective association between bioactive RBP4 and TLR2. TLR2 antagonist C29 reversed the effects of rRBP4 in vitro and in vivo. We conclude that decreased plasma RBP4 reflects the occurrence of infection rather than sepsis. Plasma RBP4 is protective in KPS likely through TLR2-dependent stimulation of neutrophils.