Cutting Edge: A Critical Role for the G Protein-Coupled Receptor mFPR2 in Airway Inflammation and Immune Responses

Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Maryland, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2010; 184(7):3331-5. DOI: 10.4049/jimmunol.0903022
Source: PubMed


The formylpeptide receptor-like 1, now officially termed FPR2, in human and its mouse homolog mFPR2 mediate leukocyte migration in response to agonists associated with inflammation and immune responses. To clarify the in vivo role of the receptor, we generated mice deficient in mFPR2. mFPR2(-/-) mice showed markedly reduced severity in OVA/alum-induced allergic airway inflammation. This was associated with diminished recruitment of CD11c(+) dendritic cells into the airway mucosa and secondary lymphoid organs, as well as reduced production of Type 2 cytokines and Igs. We also found that the bronchoalveolar lavage fluid from wild type mice with airway inflammation contained mFPR2 agonist activity. This study reveals a critical role for mFPR2 in the progression of allergic airway inflammation and immune responses.

Download full-text


Available from: Yingying Le, May 25, 2015
  • Source
    • "Responses to both full length ANX-A1 and its peptides, across macrophage ERK1/2 phosphorylation in vitro as well as leukocyte migration in air-pouch and zymosan peritonitis models of inflammation, were also reduced (Dufton et al., 2010; Dalli et al., 2013). In contrast, a reduced severity of ovalbumininduced airway inflammation was observed (in direct contrast to the mFpr2/3 −/− mouse above) (Chen et al., 2010). More recently, the same investigators observed that the inflammatory responses in the early stages of experimental colitis were both accelerated and prolonged in the mFpr2 −/− mouse, with increased susceptibility to subsequent lethality compared to wild type mice (Chen et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Myocardial infarction (MI) and its resultant heart failure remains a major cause of death in the world. The current treatments for patients with MI are revascularization with thrombolytic agents or interventional procedures. These treatments have focused on restoring blood flow to the ischemic tissue to prevent tissue necrosis and preserve organ function. The restoration of blood flow after a period of ischemia, however, may elicit further myocardial damage, called reperfusion injury. Pharmacological interventions, such as antioxidant and Ca(2+) channel blockers, have shown premises in experimental settings; however, clinical studies have shown limited success. Thus, there is a need for the development of novel therapies to treat reperfusion injury. The therapeutic potential of glucocorticoid-regulated anti-inflammatory mediator annexin-A1 (ANX-A1) has recently been recognized in a range of systemic inflammatory disorders. ANX-A1 binds to and activates the family of formyl peptide receptors (G protein-coupled receptor family) to inhibit neutrophil activation, migration and infiltration. Until recently, studies on the cardioprotective actions of ANX-A1 and its peptide mimetics (Ac2-26, CGEN-855A) have largely focused on its anti-inflammatory effects as a mechanism of preserving myocardial viability following I-R injury. Our laboratory provided the first evidence of the direct protective action of ANX-A1 on myocardium, independent of inflammatory cells in vitro. We now review the potential for ANX-A1 based therapeutics to be seen as a "triple shield" therapy against myocardial I-R injury, limiting neutrophil infiltration and preserving both cardiomyocyte viability and contractile function. This novel therapy may thus represent a valuable clinical approach to improve outcome after MI. Copyright © 2014. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.012 · 9.72 Impact Factor
  • Source
    • "Five 8-10 weeks old wild type, mFPR1-/- [24], mFPR2-/- [25] C57/Bl6 mice were stimulated with 4mg/Kg bodyweight E. coli LPS (Sigma-Aldrich, Steinheim, Germany) and kept for 3 h and 6 h. The mFPR1 Mice were a kind gift from Dr. Philip Murphy of the National Institute for Allergy and Infectious Diseases, NIH [24]. "
    [Show abstract] [Hide abstract]
    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.
    PLoS ONE 06/2014; 9(6):e100522. DOI:10.1371/journal.pone.0100522 · 3.23 Impact Factor
  • Source
    • "Activation of FPRs or Fprs by their agonists elicits a signaling cascade that culminates in neutrophil migration, increased phagocytosis and release of superoxide. In mouse disease models, Fprs have recently been implicated in sustaining innate and adaptive immune responses, promoting host defense against bacterial infection by mediating rapid infiltration of neutrophils, maintaining the homeostasis of colon epithelia, and polarizing macrophages toward M1 phenotype in a malignant tumor [8], [9], [10], [11]. Therefore, FPRs (Fprs) actively participate in diverse pathophysiological processes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Wound healing is a multi-phased pathophysiological process requiring chemoattractant receptor-dependent accumulation of myeloid cells in the lesion. Two G protein-coupled formylpeptide receptors Fpr1 and Fpr2 mediate rapid neutrophil infiltration in the liver of Listeria-infected mice by sensing pathogen-derived chemotactic ligands. These receptors also recognize host-derived chemotactic peptides in inflammation and injury. Here we report the capacity of Fprs to promote the healing of sterile skin wound in mice by initiating neutrophil infiltration. We found that in normal miceneutrophils rapidly infiltrated the dermis in the wound before the production of neutrophil-specific chemokines by the injured tissue. In contrast, rapid neutrophil infiltration was markedly reduced with delayed wound closure in mice deficient in both Fprs. In addition, we detected Fpr ligand activity that chemoattracted neutrophils into the wound tissue. Our study thus demonstrates that Fprs are critical for normal healing of the sterile skin wound by mediating the first wave of neutrophil infiltration.
    PLoS ONE 03/2014; 9(3):e90613. DOI:10.1371/journal.pone.0090613 · 3.23 Impact Factor
Show more