BDKRB1 activation induces CXCR2 desensitization in neutrophils during severe sepsis and exacerbates disease severity
Raquel Duque do Nascimento Arifa, Carolina Braga Resende Mascarenhas, Lívia Caroline Resende Rossi, Maria Eduarda Freitas Silva, Larissa M. Lucas, João Paulo Pezzini Barbosa, Daiane Boff, Brenda Gonçalves Resende, Lívia Duarte Tavares, Alesandra Corte Reis, Vanessa Pinho, Flavio Almeida Amaral, Caio Tavares Fagundes, Cristiano Xavier Lima, Mauro Martins Teixeira, Daniele G Souza
Raquel Duque do Nascimento Arifa, Carolina Braga Resende Mascarenhas, Lívia Caroline Resende Rossi, Maria Eduarda Freitas Silva, Larissa M. Lucas, João Paulo Pezzini Barbosa, Daiane Boff, Brenda Gonçalves Resende, Lívia Duarte Tavares, Alesandra Corte Reis, Vanessa Pinho, Flavio Almeida Amaral, Caio Tavares Fagundes, Cristiano Xavier Lima, Mauro Martins Teixeira, Daniele G Souza
View: Text | PDF
Research Article Inflammation Microbiology

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.

Authors

Raquel Duque do Nascimento Arifa, Carolina Braga Resende Mascarenhas, Lívia Caroline Resende Rossi, Maria Eduarda Freitas Silva, Larissa M. Lucas, João Paulo Pezzini Barbosa, Daiane Boff, Brenda Gonçalves Resende, Lívia Duarte Tavares, Alesandra Corte Reis, Vanessa Pinho, Flavio Almeida Amaral, Caio Tavares Fagundes, Cristiano Xavier Lima, Mauro Martins Teixeira, Daniele G Souza

×

Figure 1

BDKRB1, but not the BDKRB2, plays a pivotal role in the pathogenesis of CLP sepsis.

Options: View larger image (or click on image) Download as PowerPoint
BDKRB1, but not the BDKRB2, plays a pivotal role in the pathogenesis of ...
WT, Bdkrb1−/−, or Bdkrb2−/− mice were subjected to sham or CLP sepsis surgery. (A) Survival of mice subjected to CLP sepsis was followed for 14 days. Results are percentage of (A) survival, analyzed by the log-rank (Mantel-Cox) test, with 10 mice/group. Six hours after CLP sepsis, groups of mice were euthanized, blood was drawn, and peritoneal lavage was performed. (B) CFUs in blood and peritoneal exudate, (C) total leukocytes, and (D) neutrophil recruitment in the peritoneal cavity were analyzed. (E) Leukocyte adhesion was analyzed 3 hours after CLP in the cremaster by intravital microscopy. Results are expressed as mean ± SEM of at least 4 animals/group. Six hours after CLP, groups of mice were euthanized, blood was drawn, and peritoneal lavage was performed. (F and G) CXCL1 and (H and I) TNF concentrations were quantified in the peritoneal lavage and serum. Experiments were replicated at least once, and 1 representative experiment is presented. Survival analysis was performed with at least 10 animals/group. The Mantel-Cox log-rank test (χ2) was used for statistical analysis of survival curves. ANOVA followed by Tukey’s multiple comparisons posttest was used for data with a normal distribution. For data that did not follow a normal distribution, the Kruskal-Wallis test followed by Dunn’s multiple comparisons posttest was applied to compare 3 or more independent groups. P < 0.05. *, P < 0.05, compared with the sham group; #, P < 0.05, compared with the WT mice subjected to CLP.