Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

Significance Sepsis defines a syndrome with poor clinical management characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state. We define an endogenous pathway centered on formyl-peptide receptor 2/3 (Fpr2/3)—ortholog to human FPR2/ALX (receptor...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2014-12, Vol.111 (52), p.18685-18690
Main Authors: Gobbetti, Thomas, Coldewey, Sina M., Chen, Jianmin, McArthur, Simon, le Faouder, Pauline, Cenac, Nicolas, Flower, Roderick J., Thiemermann, Christoph, Perretti, Mauro
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Agonists
Animals
Antibiotics
Bacteria
Biological Sciences
Chemokine CCL2 - genetics
Chemokine CCL2 - metabolism
Chemokine CXCL1 - genetics
Chemokine CXCL1 - metabolism
Cytokines
Disease Models, Animal
Granulocytes - metabolism
Granulocytes - pathology
Humans
Hypothermia
Inflammation
Mice
Mice, Knockout
Monocytes
Monocytes - metabolism
Monocytes - pathology
Neutrophils
Peptides
Peritoneum - metabolism
Peritoneum - pathology
Phagocytosis
Receptors
Receptors, Formyl Peptide - genetics
Receptors, Formyl Peptide - metabolism
Rodents
Sepsis
Sepsis - genetics
Sepsis - metabolism
Sepsis - pathology
Signal Transduction
Time Factors
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
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Summary:Significance Sepsis defines a syndrome with poor clinical management characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state. We define an endogenous pathway centered on formyl-peptide receptor 2/3 (Fpr2/3)—ortholog to human FPR2/ALX (receptor for lipoxin A4)—that protects the host against polymicrobial sepsis. Using null mice and proof-of-concept experiments with a peptide–agonist, we demonstrate how engagement of Fpr2/3 is crucial to enact nonredundant functions that span from control of cell recruitment and phagocytosis, modulation of soluble mediator generation, to containment of bacteremia, thus preventing spreading to vital organs and opening new opportunities to manipulate the host response in sepsis. 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 th
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1410938111