title: Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis.
abstract: Sepsis is characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state, defining a complex clinical scenario that explains the lack of successful therapeutic options. Here we tested whether the formyl-peptide receptor 2/3 (Fpr2/3)--ortholog to human FPR2/ALX (receptor for lipoxin A4)--exerted regulatory and organ-protective functions in experimental sepsis. Coecal ligature and puncture was performed to obtain nonlethal polymicrobial sepsis, with animals receiving antibiotics and analgesics. Clinical symptoms, temperature, and heart function were monitored up to 24 h. Peritoneal lavage and plasma samples were analyzed for proinflammatory and proresolving markers of inflammation and organ dysfunction. Compared with wild-type mice, Fpr2/3(-/-) animals exhibited exacerbation of disease severity, including hypothermia and cardiac dysfunction. This scenario was paralleled by higher levels of cytokines [CXCL1 (CXC receptor ligand 1), CCL2 (CC receptor ligand 2), and TNFα] as quantified in cell-free biological fluids. Reduced monocyte recruitment in peritoneal lavages of Fpr2/3(-/-) animals was reflected by a higher granulocyte/monocyte ratio. Monitoring Fpr2/3(-/-) gene promoter activity with a GFP proxy marker revealed an over threefold increase in granulocyte and monocyte signals at 24 h post-coecal ligature and puncture, a response mediated by TNFα. Treatment with a receptor peptido-agonist conferred protection against myocardial dysfunction in wild-type, but not Fpr2/3(-/-), animals. Therefore, coordinated physio-pharmacological analyses indicate nonredundant modulatory functions for Fpr2/3 in experimental sepsis, opening new opportunities to manipulate the host response for therapeutic development.
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Thomas
authors.initials: T
authors.lastname: Gobbetti
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07743 Jena, Germany;
authors.forename: Sina M
authors.initials: SM
authors.lastname: Coldewey
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Jianmin
authors.initials: J
authors.lastname: Chen
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Simon
authors.initials: S
authors.lastname: McArthur
authors.affiliation: MetaToul Lipidomics Facility, INSERM UMR1048, 31024 Toulouse, France; and.
authors.forename: Pauline
authors.initials: P
authors.lastname: le Faouder
authors.affiliation: INSERM UMR1043, Université Toulouse III Paul-Sabatier, 31024 Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Flower
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom;
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.affiliation: The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; m.perretti@qmul.ac.uk.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006098:Granulocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C509871:HSH2 protein, mouse; D044042:Receptors, Formyl Peptide; D014409:Tumor Necrosis Factor-alpha; C481578:formyl peptide receptor 2, mouse
keywords: ALX; annexin peptide; cardiac dysfunction; resolution of inflammation; therapeutic innovation