Deficiency of formyl peptide receptor 1 and 2 is associated with increased inflammation and enhanced liver injury after LPS-stimulation

Formyl peptide-receptor 1 and 2 (FPR1 and FPR2) in mice were identified as receptors with contrary affinity for the PAMP fMLF. Formyl-methionyl-leucyl-phenylalanine is either part of the bacterial membrane and is secreted by the mitochondria of eukaryotic ceslls during apoptosis. Furthermore FPR1 an...

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Bibliographic Details
Published in:PloS one 2014-06, Vol.9 (6), p.e100522
Main Authors: Giebeler, Arne, Streetz, Konrad L, Soehnlein, Oliver, Neumann, Ulf, Wang, Ji Ming, Brandenburg, Lars-Ove
Format: Article
Language:English
Subjects:
Analysis
Animals
Apoptosis
Bacteria
Bacterial infections
Biology and Life Sciences
Cancer
CD11b antigen
Cell Proliferation
Cells, Cultured
Chemotaxis
Clonal deletion
Cytokines
Deregulation
Formyl peptides
Gene expression
Genotypes
Hepatocytes
Immune system
Immunoenzyme Techniques
Inflammation
Inflammation - etiology
Inflammation - metabolism
Inflammation - pathology
Inflammation Mediators - metabolism
Inflammatory response
Injuries
Interleukin 6
Lipopolysaccharides
Lipopolysaccharides - toxicity
Liver
Liver - injuries
Liver - metabolism
Liver - pathology
Liver diseases
Male
Medicine and Health Sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
Mitochondrial DNA
Neutrophils
Nuclei
Nuclei (cytology)
Peptides
Phenylalanine
Real-Time Polymerase Chain Reaction
Receptors
Receptors, Formyl Peptide - physiology
Research and Analysis Methods
Reverse Transcriptase Polymerase Chain Reaction
Risk factors
RNA, Messenger - genetics
Rodents
Stimulation
TLR2 protein
TLR4 protein
Toll-like receptors
Transaminases
Tumor necrosis factor-α
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Summary:Formyl peptide-receptor 1 and 2 (FPR1 and FPR2) in mice were identified as receptors with contrary affinity for the PAMP fMLF. Formyl-methionyl-leucyl-phenylalanine is either part of the bacterial membrane and is secreted by the mitochondria of eukaryotic ceslls during apoptosis. Furthermore FPR1 and 2 are described as highly relevant factors for the chemotaxis of immune cells. Their role during the acute liver injury has not been investigated yet. Constitutive knockout mice for FPR1 (mFPR1-/-), FPR2 (mFPR2-/-) and wild type (WT) mice were challenged with LPS i.p. for 3 h and 6 h. Liver and serum were sampled for further analysis. Liver transaminases were elevated in all mice 3 h and 6 h post LPS stimulation. Gene expression analysis displayed a reduced expression of the pro-inflammatory cytokines IL-6 and CXCL1 after 3 h in the mFPR1-/- compared to wild type and mFPR2-/- mice. After 6 h, IL-6, TNF-α and CXCL1 were significantly higher in mice lacking mFPR1 or 2. Consistent to these findings the numbers of CD11b+ and Ly6G+ immune cells were altered in the livers. The analysis of TLR2 and TLR4 revealed time and genotype specific changes in theirs gene expression. Additionally, the liver in mFPR1- and mFPR2-deficient mice seem to be more susceptible to apoptosis by showing a significant higher number of TUNEL+-cells in the liver than WT-mice and displayed less Ki67-positive nuclei in the liver. The results suggest a prominent role of FPRs in the regulation of the hepatic inflammatory response after LPS induced liver injury. Deletion of mFPR1 or mFPR2 leads to deregulation of the inflammatory response compared to WT mice, associated with more severe liver injury represented by higher levels of transaminases, apoptotic cells and a reduced regenerative capacity.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0100522