Inhibitory role of the acute phase proteins on neutrophil migration in severe sepsis

Reduction of neutrophil migration to infection sites correlates with bad outcome in sepsis. Acute phase proteins (APPs) were described to inhibit the neutrophil functions, such as neutrophil migration. We recently showed that α₁-acid glycoprotein (AGP) is a serum factor involved in neutrophil migration failure in human severe sepsis. In mouse experimental sepsis, the serum AGP concentration was significantly increased only 6 hours after severe sepsis. However, 2 hours after severe sepsis induction in mice, essential steps for neutrophil migration are disrupt, such as a decrease on rolling and adhesion of leukocytes to the endothelium and less of the chemokine receptor CXCR2 expression on the neutrophil membrane. Therefore, AGP should not be involved in early steps of severe sepsis development. The identification of these other serum factors involved in the neutrophil migration failure could be helpful for appropriate management of severe sepsis. In this context, the objective of the present study was to identify soluble substances in the blood of septic mice that inhibit neutrophil migration in the early steps of sepsis. One pool of serum, obtained 2 hours after polymicrobial severe sepsis induction in mice, partially inhibited thioglycolate-induced neutrophil migration into the peritoneal cavity of naïve mice. Separation and identification by Blue-Sepharose, HPLC, native electrophoresis and mass spectrometry of soluble substances with inhibitory activity on neutrophil migration in this serum showed the APP hemopexin (Hx). The purified Hx, as well as the commercial sample of Hx, inhibited thioglycolate-induced or sepsis-induced neutrophil migration to the peritoneal cavity of mice. In contrast to wild-type mice, Hx-null mice that underwent severe sepsis did not present failure of neutrophil migration to infectious focus. As a consequence, these animals presented low bacteremia and high survival rate. Furthermore, Hx inhibited the neutrophil chemotaxis response evoked by C5a or MIP-2 and induces downmodulation of the CXCR2 and L-selectin. These results showed an inhibitory role of the APPs on neutrophil migration in sepsis and suggest that species-specific and time-specific inhibition of the APPs activities may be a new strategy for sepsis treatment.