Activation of bradykinin receptor B1 promotes desensitization of CXCR2 in neutrophils during severe sepsis and contributes to disease progression in mice.

Sepsis is one of the most common causes of death in intensive care units. The overproduction of proinflammatory mediators during severe sepsis leads to desensitization of CXCR2 on neutrophil, compromising their migration capacity. During early sepsis, kinins are released and bind to bradykinin 1 (BDKRB1) and bradykinin 2 (BDKRB2) receptors, however the involvement of these receptors in sepsis is not yet fully understood. This study demonstrated that the absence of BDKRB2 had no major effects compared to WT mice upon sepsis induction by CLP, suggesting that this receptor plays a minor role under these experimental conditions. In contrast, B1 -/- mice showed lower mortality and bacterial recovery compared to WT-CLP mice, which was associated with an increased influx of neutrophils into the peritoneal cavity of CLP-B1 -/- mice. WT-CLP mice exhibited increased expression of P110 gamma and decreased expression of CXCR2 in neutrophils, which was partially reversed in CLP-B1 -/- mice. Interestingly, local CXCL1 production was not affected by the absence of BDKRB1. In human neutrophils, LPS induced expression of BDKRB1, and antagonism of this receptor was associated with the restoration of neutrophil recruitment capacity upon stimulation with CXCL8. Furthermore, treatment with a BDKRB1 antagonist in combination with imipenem resulted in a significant improvement in mortality compared to animals treated with the antimicrobial agent alone. Our findings demonstrate that BDKRB1 plays an essential role in exacerbating the inflammatory response and CXCR2 desensitization in neutrophils during CLP-induced severe sepsis, highlighting BDKRB1 as a potential target for sepsis treatment.