Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Tancevski, I; Nairz, M; Duwensee, K; Auer, K; Schroll, A; Heim, C; Feistritzer, C; Hoefer, J; Gerner, RR; Moschen, AR; Heller, I; Pallweber, P; Li, X; Theurl, M; Demetz, E; Wolf, AM; Wolf, D; Eller, P; Ritsch, A; Weiss, G.
Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2.
EMBO Mol Med. 2014; 6(6):810-820
Doi: 10.1002/emmm.201303415
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- Co-Autor*innen der Med Uni Graz
- Eller Philipp
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- Abstract:
- 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. © 2014 The Authors. Published under the terms of the CC BY license.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Bacteremia - drug therapy
- Bacteremia - immunology
- Fibric Acids - therapeutic use
- Immunity, Innate - drug effects
- Lipopolysaccharides - immunology
- Male -
- Mice -
- Mice, Inbred C57BL -
- Neutrophil Infiltration - drug effects
- PPAR gamma - immunology
- Receptors, Interleukin-8B - immunology
- Salmonella Infections - drug therapy
- Salmonella Infections - immunology
- Salmonella typhimurium - drug effects
- Find related publications in this database (Keywords)
- chemokine receptor
- fenofibrate
- infection
- inflammation
- neutrophils