Serum Amyloid A Is a Chemotactic Agonist at FPR2, a Low-Affinity N-Formylpeptide Receptor on Mouse Neutrophils

doi:10.1006/bbrc.2000.2416

Biochemical and Biophysical Research Communications

Volume 270, Issue 2, 13 April 2000, Pages 331-335

https://doi.org/10.1006/bbrc.2000.2416 Get rights and content

Abstract

Serum amyloid A (SAA) is an acute-phase plasma protein and the source of amyloid A, which accumulates in lesions of secondary amyloidosis. SAA can induce phagocyte migration in vitro and in vivo, and is a specific chemotactic agonist for the human low-affinity N-formylpeptide receptor FPRL1R, a G-protein-coupled receptor expressed on phagocytes. Here we show that FPR2, a mouse counterpart of FPRL1R, is also an SAA receptor. SAA selectively induced calcium flux and chemotaxis in mouse PMN, which express FPR2, as well as in HEK 293 cells expressing recombinant FPR2 but not in HEK 293 cells expressing FPR, a closely related high affinity N-formylpeptide receptor. Consistent with this, SAA activity on PMN from FPR+/+ and FPR−/− mice was indistinguishable. Moreover, the prototype N-formylpeptide fMLF desensitized SAA-induced calcium flux in a dose-dependent manner in both mouse neutrophils and HEK 293/FPR2 transfectants. Our results suggest that FPR2 specifically mediates mouse neutrophil migration in response to SAA.

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Formyl peptide receptor 2 (FPR2) and its mouse counterpart Fpr2 are the members of the G protein-coupled receptor (GPCR) family. FPR2 is the only member of the FPRs that interacts with ligands from different sources. FPR2 is expressed in myeloid cells as well as epithelial cells, endothelial cells, neurons, and hepatocytes. During the past years, some unusual properties of FPR2 have attracted intense attention because FPR2 appears to possess dual functions by activating or inhibiting intracellular signal pathways based on the nature, concentration of the ligands, and the temporal and spatial settings of the microenvironment in vivo, the cell types it interacts with. Therefore, FPR2 controls an abundant array of developmental and homeostatic signaling cascades, in addition to its “classical” capacity to mediate the migration of hematopoietic and non-hematopoietic cells including malignant cells. In this review, we summarize recent development in FPR2 research, particularly in its role in diseases, therefore helping to establish FPR2 as a potential target for therapeutic intervention.
Selective FPR2 Agonism Promotes a Proresolution Macrophage Phenotype and Improves Cardiac Structure-Function Post Myocardial Infarction
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Citation Excerpt :
In the HL-60 FPR2 KO line, no enhancement in chemotaxis with BMS-986235 was obtained. When HL-60 cells were pretreated with BMS-986235, chemotaxis toward serum amyloid A (SAA), a potent proinflammatory apolipoprotein and a known ligand for FPR2 (16), was inhibited with a half maximal inhibitory concentration value of 21 nM. A similar antagonist profile was obtained with FPR1-deficient HL-60 cells (half maximal inhibitory concentration = 14 nM).
Dysregulated inflammation following myocardial infarction (MI) leads to maladaptive healing and remodeling. The study characterized and evaluated a selective formyl peptide receptor 2 (FPR2) agonist BMS-986235 in cellular assays and in rodents undergoing MI. BMS-986235 activated G proteins and promoted β-arrestin recruitment, enhanced phagocytosis and neutrophil apoptosis, regulated chemotaxis, and stimulated interleukin-10 and monocyte chemoattractant protein-1 gene expression. Treatment with BMS-986235 improved mouse survival, reduced left ventricular area, reduced scar area, and preserved wall thickness. Treatment increased macrophage arginase-1 messenger RNA and CD206 receptor levels indicating a proresolution phenotype. In rats following MI, BMS-986235 preserved viable myocardium, attenuated left ventricular remodeling, and increased ejection fraction relative to control animals. Therefore, FPR2 agonism improves post-MI healing, limits remodeling and preserves function, and may offer an innovative therapeutic option to improve outcomes.
SAA1/TLR2 axis directs chemotactic migration of hepatic stellate cells responding to injury
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Hepatic stellate cells (HSCs) are crucial for liver injury repair and cirrhosis. However, the mechanism of chemotactic recruitment of HSCs into injury loci is still largely unknown. Here, we demonstrate that serum amyloid A1 (SAA1) acts as a chemokine recruiting HSCs toward injury loci signaling via TLR2, a finding proven by gene manipulation studies in cell and mice models. The mechanistic investigations revealed that SAA1/TLR2 axis stimulates the Rac GTPases through PI3K-dependent pathways and induces phosphorylation of MLC (pSer19). Genetic deletion of TLR2 and pharmacological inhibition of PI3K diminished the phosphorylation of MLCpSer19 and migration of HSCs. In brief, SAA1 serves as a hepatic endogenous chemokine for the TLR2 receptor on HSCs, thereby initiating PI3K-dependent signaling and its effector, Rac GTPases, which consequently regulates actin filament remodeling and cell directional migration. Our findings provide novel targets for anti-fibrosis drug development.
Preservation of Post-Infarction Cardiac Structure and Function via Long-Term Oral Formyl Peptide Receptor Agonist Treatment
2019, JACC: Basic to Translational Science
Dysregulated inflammation following myocardial infarction (MI) promotes left ventricular (LV) remodeling and loss of function. Targeting inflammation resolution by activating formyl peptide receptors (FPRs) may limit adverse remodeling and progression towards heart failure. This study characterized the cellular and signaling properties of Compound 43 (Cmpd43), a dual FPR1/FPR2 agonist, and examined whether Cmpd43 treatment improves LV and infarct remodeling in rodent MI models. Cmpd43 stimulated FPR1/2-mediated signaling, enhanced proresolution cellular function, and modulated cytokines. Cmpd43 increased LV function and reduced chamber remodeling while increasing proresolution macrophage markers. The findings demonstrate that FPR agonism improves cardiac structure and function post-MI.
Cytokines and serum amyloid A in the pathogenesis of hepatitis C virus infection
2019, Cytokine and Growth Factor Reviews
Expression of the acute phase protein serum amyloid A (SAA) is dependent on the release of the pro-inflammatory cytokines IL-1, IL-6 and TNF-α during infection and inflammation. Hepatitis C virus (HCV) upregulates SAA-inducing cytokines. In line with this, a segment of chronically infected individuals display increased circulating levels of SAA. SAA has even been proposed to be a potential biomarker to evaluate treatment efficiency and the course of disease. SAA possesses antiviral activity against HCV via direct interaction with the viral particle, but might also divert infectivity through its function as an apolipoprotein. On the other hand, SAA shares inflammatory and angiogenic activity with chemotactic cytokines by activating the G protein-coupled receptor, formyl peptide receptor 2. These latter properties might promote chronic inflammation and hepatic injury. Indeed, up to 80 % of infected individuals develop chronic disease because they cannot completely clear the infection, due to diversion of the immune response. In this review, we summarize the interconnection between SAA and cytokines in the context of HCV infection and highlight the dual role SAA could play in this disease. Nevertheless, more research is needed to establish whether the balance between those opposing activities can be tilted in favor of the host defense.
Serum Amyloid A1 Is an Epithelial Prorestitutive Factor
2018, American Journal of Pathology
Citation Excerpt :
Previous studies have demonstrated that SAA1 promotes chemotaxis in neutrophils through FPR2, rather than FPR1, signaling. Therefore, the FPR2-specific receptor antagonist WRW43,17,18 and the FPR1 receptor antagonist cyclosporine H15 were used. Cells treated with WRW4 demonstrated markedly reduced wound closure compared with control cells (Figure 3, A and B).
Several proteins endogenously produced during the process of intestinal wound healing have demonstrated prorestitutive properties. The presence of serum amyloid A1 (SAA1), an acute-phase reactant, within inflamed tissues, where it exerts chemotaxis of phagocytes, is well recognized; however, a putative role in intestinal wound repair has not been described. Herein, we show that SAA1 induces intestinal epithelial cell migration, spreading, and attachment through a formyl peptide receptor 2–dependent mechanism. Induction of the prorestitutive phenotype is concentration and time dependent and is associated with epithelial reactive oxygen species production and alterations in p130 Crk-associated substrate staining. In addition, using a murine model of wound recovery, we provide evidence that SAA1 is dynamically and temporally regulated, and that the elaboration of SAA1 within the wound microenvironment correlates with the influx of SAA1/CD11b coexpressing immune cells and increases in cytokines known to induce SAA expression. Overall, the present work demonstrates an important role for SAA in epithelial wound recovery and provides evidence for a physiological role in the wound environment.

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¹: To whom correspondence should be addressed at Laboratory of Host Defenses, NIAID, Building 10, Room 11N113, National Institutes of Health, Bethesda, MD 20892. Fax: 301-402-4269. E-mail: [email protected].

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Regular ArticleSerum Amyloid A Is a Chemotactic Agonist at FPR2, a Low-Affinity N-Formylpeptide Receptor on Mouse Neutrophils

Abstract

Immunol. Today

J. Lipid Res.

Medical Hypotheses

Blood

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Genomics

Genomics

Regulation of serum amyloid A protein expression during the acute-phase response

Biochem. J.

The acute-phase response

Expression of apolipoprotein serum amyloid A mRNA in human atherosclerotic lesions and cultured vascular cells: Implications for serum amyloid A function

Proc. Natl. Acad. Sci. USA

Regular Article
Serum Amyloid A Is a Chemotactic Agonist at FPR2, a Low-Affinity N-Formylpeptide Receptor on Mouse Neutrophils