Berberine in combination with yohimbine attenuates sepsis-induced neutrophil tissue infiltration and multiorgan dysfunction partly via IL-10-mediated inhibition of CCR2 expression in neutrophils

Abstract Infiltration of activated neutrophils into the vital organs contributes to the multiple organ dysfunctions in sepsis. In the present study, we investigated the effects of berberine in combination with yohimbine (BY) on neutrophil tissue infiltration and multiple organ damage during sepsis, and further elucidated the involved mechanisms. Sepsis was induced in mice by cecal ligation and puncture (CLP). BY or CCR2 antagonist was administered 2 h after CLP, and anti-IL-10 antibody (IL-10 Ab) or control IgG was injected intraperitoneally just before BY treatment. We found that IL-10 production was enhanced by BY therapy in septic mice. BY significantly attenuated neutrophil tissue infiltration and multiple organ injury in CLP-challenged mice, all of which were completely reversed by IL-10 Ab pretreatment. The levels of KC, MCP-1, MIP-1α and MIP-2 in the lung, liver and kidney were markedly increased 6 h after CLP. BY reduced the tissue concentrations of these chemokines in septic mice, but IL-10 Ab pretreatment did not completely eliminate these inhibitory effects of BY. Particularly, dramatically increased CCR2 expression in circulating neutrophils of septic mice was reduced by BY and this effect was completely abolished by IL-10 Ab pretreatment. Furthermore, CCR2 antagonist also inhibited lung and renal injury and neutrophil infiltration in septic mice. Taken together, our data strongly suggest that BY therapy attenuates neutrophil tissue infiltration and multiple organ injury in septic mice, at least in part, via IL-10-mediated inhibition of CCR2 expression in circulating neutrophils.