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Giebeler, Arne; Streetz, Konrad L.; Soehnlein, Oliver; Neumann, Ulf; Wang, Ji Ming and Brandenburg, Lars-Ove (2014): Deficiency of Formyl Peptide Receptor 1 and 2 Is Associated with Increased Inflammation and Enhanced Liver Injury after LPS-Stimulation.
In: PLOS ONE 9(6), e100522 [PDF, 1MB]

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Introduction: 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. Materials and Methods: 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. Results: 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-alpha 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. Conclusion: 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.

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