一种非杀菌性抗菌肽通过调节抗菌免疫和血管内皮功能对细菌性脓毒症提供保护作用

The anti-infective properties of bactericidal antimicrobial peptides (AMPs) have been extensively studied, but less information is available regarding the role and mechanisms of action of non­bactericidal AMPs in sepsis. Herein, a novel β-sheet cathelicidin antimicrobial peptide (Og-CATH) was identified from the frog Odorrana grahami. Intriguingly, Og-CATH showed no direct antimicrobial activity in vitro, but displayed prophylactic and therapeutic efficacy in Staphylococcus aureus, Enterobacteriaceae coli, or cecal ligation and puncture-induced septic mice. Neutrophils and monocytes/macrophages, but not T/B lymphocytes, were required for the protective efficacy of Og-CATH in mice. Og-CATH did not exhibit a direct chemoattractant effect on phagocytes, but it promoted macrophages and neutrophils trafficking to the infection site via chemokines secreted by P2X7 receptor-activated macrophages, and augmented their oxygen-independent bacterial killing functions via the enhancement of phagocytosis and neutrophils degranulation. Of note, Og-CATH also inhibited the production of tissue factor, a potent initiator of the extrinsic coagulation cascade, and up-regulated the expression of activated protein C, a physiological anticoagulant both in endothelial cells and in mice, which contribute to the reduction of pulmonary fibrin deposition and thrombosis in mice. Further investigation revealed that Og-CATH targeted the myeloid differentiation protein 2 (MD2), and inhibited the LPS-induced MyD88 recruitment to TLR4 in endothelial cells, thus attenuating endothelial barrier dysfunction during sepsis. Our data indicated that Og-CATH provides protective effects against sepsis through regulation of phagocytes and endothelial functions. These findings enrich our understanding of the anti-infection mechanism of non­bactericidal AMPs, and show that Og-CATH is an excellent candidate for further therapeutic development of sepsis.