These authors contributed equally to this study.
Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2
Article first published online: 22 APR 2014
© 2014 The Authors. Published under the terms of the CC BY license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 6, Issue 6, pages 810–820, June 2014
How to Cite
EMBO Mol Med (2014) 6: 810–820
- Issue published online: 3 JUN 2014
- Article first published online: 22 APR 2014
- Manuscript Accepted: 11 MAR 2014
- Manuscript Revised: 7 MAR 2014
- Manuscript Received: 21 AUG 2013
- chemokine receptor;
Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate-mediated early control of infection, the systemic inflammatory response was repressed in fibrate-treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS-induced phosphorylation of ERK. This results in a decrease of G protein-coupled receptor kinase-2 expression, thereby inhibiting the LPS-mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis.
In this study, fibrates are shown to protect against bacteria-induced sepsis by promoting neutrophil influx to the primary site of infection, aiding in an efficient elimination of bacteria, and contributing to improved clinical outcomes from sepsis.
- Survival of septic mice infected with Salmonella typhimurium is improved through treatment with fibrates.
- Increased migratory efficiency of neutrophils results in early clearance of bacteria.
- Expression of chemokine receptor CXCR2 on neutrophils in sepsis is preserved.
- CXCR2 expression is maintained through a ERK/GRK2-dependent mechanism.