title: Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2.
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.
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria ivan.tancevski@i-med.ac.at guenter.weiss@i-med.ac.at.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tancevski
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Manfred
authors.initials: M
authors.lastname: Nairz
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Kristina
authors.initials: K
authors.lastname: Duwensee
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Kristina
authors.initials: K
authors.lastname: Auer
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Christiane
authors.initials: C
authors.lastname: Heim
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Feistritzer
authors.affiliation: Department of Urology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoefer
authors.affiliation: Department of Internal Medicine I/Gastroenterology, Endocrinology & Metabolism Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Romana R
authors.initials: RR
authors.lastname: Gerner
authors.affiliation: Department of Internal Medicine I/Gastroenterology, Endocrinology & Metabolism Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Moschen
authors.affiliation: Department of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Heller
authors.affiliation: Department of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Pallweber
authors.affiliation: Department of Pharmacology, Capital Medical University, Beijing, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Internal Medicine III/Cardiology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Theurl
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Egon
authors.initials: E
authors.lastname: Demetz
authors.affiliation: Department of Hematology/Oncology, University Hospital Bonn, Bonn, Germany.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Wolf
authors.affiliation: Department of Hematology/Oncology, University Hospital Bonn, Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wolf
authors.affiliation: Department of Internal Medicine/Angiology, Medical University of Graz, Graz, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Eller
authors.affiliation: Department of Internal Medicine I/Gastroenterology, Endocrinology & Metabolism Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ritsch
authors.affiliation: Department of Internal Medicine VI/Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria ivan.tancevski@i-med.ac.at guenter.weiss@i-med.ac.at.
authors.forename: Guenter
authors.initials: G
authors.lastname: Weiss
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000188:drug therapy* / Q000276:immunology; D058607:Fibric Acids / Q000627:therapeutic use*; D007113:Immunity, Innate / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects*; D047495:PPAR gamma / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000276:immunology*; D012480:Salmonella Infections / Q000188:drug therapy* / Q000276:immunology; D012486:Salmonella typhimurium / Q000187:drug effects
chemical_list: D058607:Fibric Acids; D008070:Lipopolysaccharides; D047495:PPAR gamma; D023063:Receptors, Interleukin-8B
keywords: chemokine receptor; fenofibrate; infection; inflammation; neutrophils
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