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

Giebeler A, Streetz KL, Soehnlein O, Neumann U, Wang JM, Brandenburg LO - PLoS ONE (2014)

Bottom Line: Furthermore FPR1 and 2 are described as highly relevant factors for the chemotaxis of immune cells.The analysis of TLR2 and TLR4 revealed time and genotype specific changes in theirs gene expression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University Hospital RWTH Aachen University, Aachen, Germany.

ABSTRACT

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-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.

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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Related in: MedlinePlus

To better understand mechanism underlying the infiltration of immune cells into the liver of mFPR-deficient mice the gene expression of the pro-inflammatory cytokines IL-6 (A), TNF-α (B), CXCL1 (C), TLR2 (D) and TLR4 (E) were analyzed by qPCR.Changes in gene expression were related to GAPDH as a housekeeping gene. (* = p<0.05; ** = p<0.01; # = p<0.0001.)
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pone-0100522-g004: To better understand mechanism underlying the infiltration of immune cells into the liver of mFPR-deficient mice the gene expression of the pro-inflammatory cytokines IL-6 (A), TNF-α (B), CXCL1 (C), TLR2 (D) and TLR4 (E) were analyzed by qPCR.Changes in gene expression were related to GAPDH as a housekeeping gene. (* = p<0.05; ** = p<0.01; # = p<0.0001.)

Mentions: The analysis of cytokine gene expression was contradictory between the two analysed time points. At 3 h post LPS injection an increased expression for the IL-6 gene could be detected in the WT mice compared to the mFPR1-/- mice, who showed a significantly lower expression of IL-6 mRNA (p<0.01) whereas the mFPR2-/- mice had a significantly higher expression compared to WT-mice (p<0.01). At 6 h post LPS injection the expression of IL-6 was significantly lower in the wild type animals compared to mFPR1 (p<0.05) and mFPR2-deficient mice (p<0.05). The expression of TNF-α (Fig. 4B) was significantly increased in the mFPR1 (p<0.05) and mFPR2-deficient mice (p<0.001) compared to the WT mice 3 h as well as 6 h after LPS-administration. Correlated to IL-6 gene expression also the cytokine CXCL1 displayed divergent levels of mRNA expression. At 3 h after LPS-stimulation CXCL1 has a higher expression in WT-mice compared to mFPR1-/- and mFPR2-/-. The tendency did not reach a level of significance. At 6 h post LPS injection mFPR1-knockout and mFPR2-knockout mice displayed a significant higher expression of CXCL1 compared to wild type mice (fig. 4C).


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

Giebeler A, Streetz KL, Soehnlein O, Neumann U, Wang JM, Brandenburg LO - PLoS ONE (2014)

To better understand mechanism underlying the infiltration of immune cells into the liver of mFPR-deficient mice the gene expression of the pro-inflammatory cytokines IL-6 (A), TNF-α (B), CXCL1 (C), TLR2 (D) and TLR4 (E) were analyzed by qPCR.Changes in gene expression were related to GAPDH as a housekeeping gene. (* = p<0.05; ** = p<0.01; # = p<0.0001.)
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4067326&req=5

pone-0100522-g004: To better understand mechanism underlying the infiltration of immune cells into the liver of mFPR-deficient mice the gene expression of the pro-inflammatory cytokines IL-6 (A), TNF-α (B), CXCL1 (C), TLR2 (D) and TLR4 (E) were analyzed by qPCR.Changes in gene expression were related to GAPDH as a housekeeping gene. (* = p<0.05; ** = p<0.01; # = p<0.0001.)
Mentions: The analysis of cytokine gene expression was contradictory between the two analysed time points. At 3 h post LPS injection an increased expression for the IL-6 gene could be detected in the WT mice compared to the mFPR1-/- mice, who showed a significantly lower expression of IL-6 mRNA (p<0.01) whereas the mFPR2-/- mice had a significantly higher expression compared to WT-mice (p<0.01). At 6 h post LPS injection the expression of IL-6 was significantly lower in the wild type animals compared to mFPR1 (p<0.05) and mFPR2-deficient mice (p<0.05). The expression of TNF-α (Fig. 4B) was significantly increased in the mFPR1 (p<0.05) and mFPR2-deficient mice (p<0.001) compared to the WT mice 3 h as well as 6 h after LPS-administration. Correlated to IL-6 gene expression also the cytokine CXCL1 displayed divergent levels of mRNA expression. At 3 h after LPS-stimulation CXCL1 has a higher expression in WT-mice compared to mFPR1-/- and mFPR2-/-. The tendency did not reach a level of significance. At 6 h post LPS injection mFPR1-knockout and mFPR2-knockout mice displayed a significant higher expression of CXCL1 compared to wild type mice (fig. 4C).

Bottom Line: Furthermore FPR1 and 2 are described as highly relevant factors for the chemotaxis of immune cells.The analysis of TLR2 and TLR4 revealed time and genotype specific changes in theirs gene expression.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University Hospital RWTH Aachen University, Aachen, Germany.

ABSTRACT

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-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.

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.

Show MeSH
Related in: MedlinePlus