Deficiency of Formyl Peptide Receptor 1 and 2 Is Associated with Increased Inflammation and Enhanced Liver Injury after LPS-Stimulation

Abstract

IntroductionFormyl 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 MethodsConstitutive 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.ResultsLiver 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.ConclusionThe 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.

Intrathecal application of the antimicrobial peptide CRAMP reduced mortality and neuroinflammation in an experimental model of pneumococcal meningitis

“…This is in line with recent data showing that FPR deficiency results in a strong increase of inflammation in the CNS after pneumococcal infection and in the liver after LPS treatment. 13,38 Involvement of TLR2 is underlined by the fact that deficiency of TLR2 e which is involved in the detection of Gram-positive bacteria such as S. pneumoniae e resulted in increased bacterial load and higher mortality after pneumococcal meningitis. 39 Altogether, our results indicate that CRAMP infusion induced the detection of pathogens by PRR.…”

Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives

“…Recently it was found that bile acids can also activate ryanodine receptors [155], which are the major cellular mediator of calcium-induced calcium release. Although current studies shown a role of FPR in liver injury (e.g., [156]), involvement of bile acids as FPR1 ligands in liver pathology is still unknown. Indeed, endogenous bile acids can reduce liver neutrophil infiltration and prevent hepatotoxicity, which is similar to effects of the FPR1 antagonist Boc-1 [157].…”

Serum Amyloid A3 Secreted by Preosteoclasts Inhibits Parathyroid Hormone-stimulated cAMP Signaling in Murine Osteoblasts

“…Fpr2 has been discussed as an attractive therapeutic target but it has multiple ligands, stimulates multiple signal transduction pathways, depending on the ligand and the cell type involved, and mediates both pro-and anti-inflammatory responses (51). Several studies in Fpr2-deficient mice suggest that Fpr2 deficiency can worsen inflammation and tumorigenesis (52)(53)(54). Hence, it might be best to target the ligand rather than receptor.…”