BDKRB1 activation induces CXCR2 desensitization in neutrophils during severe sepsis and exacerbates disease severity.

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. During early sepsis, kinins are released and bind to B1 (BDKRB1) and B2 (BDKRB2) bradykinin receptors, but the involvement of these receptors in sepsis remains incompletely understood. This study demonstrated that the genetic deletion of Bdkrb2 had no significant impact on sepsis induced by cecal ligation and puncture (CLP) compared to wild-type (WT) mice. In contrast, Bdkrb1-/- mice subjected to CLP exhibited decreased lethality and bacterial load, associated with an increased influx of neutrophils into the peritoneal cavity, compared with WT mice. Neutrophils from CLP-Bdkrb1-/- mice partially restored CXCR2 expression and reduced the upregulation of P110γ observed in WT CLP neutrophils. Pharmacologic inhibition of BDKRB1 combined with imipenem treatment substantially improved survival compared with antibiotic therapy alone. In human neutrophils, stimulation with LPS led to the upregulation of BDKRB1 expression, and antagonism of BDKRB1 restored neutrophil migration in response to CXCL8. These findings identify BDKRB1 as an important modulator of neutrophil dysfunction in sepsis and a promising therapeutic target whose inhibition improves bacterial clearance, restores neutrophil migration, and increases the efficacy of antibiotic treatment.