FPR2 signaling without β-arrestin recruitment alters the functional repertoire of neutrophils

Gabl, Michael; Holdfeldt, André; Sundqvist, Martina; Lomei, Jalal; Dahlgren, Cláes; Forsman, Huamei

doi:10.1016/j.bcp.2017.08.018

Cited by 49 publications

(124 citation statements)

References 42 publications

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“…Further, neutrophils activated with Act-389949 were not only desensitized in their response to a second dose of Act-389949, but also non-responsive to the FPR2 agonist WKYMVM but fully responsive to the FPR1 agonist fMLF ( Fig 3E). In agreement with the [Ca 2+ ]i data obtained with the Gaq inhibitor ( Fig 2D), the neutrophil NADPH-oxidase response to the FPR2 agonists WKYMVM, Act-389949 or the FPR2 biased lipopeptide (pepducin) F2Pal10 [28] was not affected by the Gaq inhibitor YM-254890 ( Fig 3F). Taken together, these data demonstrate that Act-389949 is a potent and full FPR2 agonist that activates the neutrophil NADPH-oxidase independent of Gaq.…”

Section: Act-389949 Triggers An Fpr2-dependent Release Of Superoxide supporting

confidence: 88%

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Lind

Sundqvist

Holmdahl

et al. 2019

Preprint

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Despite the steadily increased numbers of formyl peptide receptor (FPR) ligands identified over the years, few have been characterized in studies using animal disease models and even less have entered clinical trials in human subjects. A small-molecule compound, Act-389949, was however recently tested in a phase I clinical trial and found to be safe and well tolerated in healthy human subjects. The desired anti-inflammatory property of Act-389949 was proposed to be mediated through FPR2, one of the FPRs expressed in neutrophils, but no basic characterization was included in the study. To gain more insights into FPR2 recognition of this first-in-class compound for future utility of the agonist, we have in this study determined the receptor preference and down-stream signaling characteristics induced by Act-389949 in human blood neutrophils isolated from healthy donors. Our data demonstrate that Act-389949 is an agonist for FPR2 that triggers functional/signaling repertoires comparable to what has been earlier described for other FPR2 agonists, including neutrophil chemotaxis, granule mobilization and activation of the NADPH-oxidase. In fact, Act-389949 was found to be as potent as the prototype FPR2 peptide agonist WKYMVM and had the advantage of being resistant to oxidation by the MPO-H2O2-halide derived oxidants, as compared to the sensitive WKYMVM. The down-stream signals generated by Act-389949 include an FPR2-dependent and Gαq-independent transient rise in intracellular Ca 2+ and recruitment of β-arrestin. In summary, our data show that Act-389949 serves as an excellent tool-compound for further dissection of FPR2-regulated activities in vitro and in vivo. Potent and stable FPR ligands such as Act-389949 may therefore be used to develop the next generation of FPR signaling regulating anti-inflammatory therapeutics.

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Section: Act-389949 Triggers An Fpr2-dependent Release Of Superoxide supporting

confidence: 88%

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Lind

Sundqvist

Holmdahl

et al. 2019

Preprint

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“…OC-STAMP is another vital factor that positively modulates cell-cell fusion independently of DC-STMAP. 28 This peptide has better affinity and low immunogenicity compared with the other FPR2 agonists. Among the pathogenesis of inflammatory osteolytic diseases, lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, was closely related to bone destruction and resorption.…”

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confidence: 99%

“…Moreover, the anti-inflammatory properties of this peptide have recently been recognized and its inhibitory activity on the production of inflammatory cytokines, such as interleukin (IL)-1β and TNF-α, has been demonstrated. 28 This peptide has better affinity and low immunogenicity compared with the other FPR2 agonists. Therefore, it may have better efficiency to regulate osteoclastogenesis in inflammatory environment and better foreground to research the application of FPR2 in orthopaedics.…”

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confidence: 99%

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

Chen

et al. 2019

J Cellular Molecular Medi

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The balance between bone formation and bone resorption is closely related to bone homeostasis. Osteoclasts, originating from the monocyte/macrophage lineage, are the only cell type possessing bone resorption ability. Osteoclast overactivity is thought to be the major reason underlying osteoclast‐related osteolytic problems, such as Paget's disease, aseptic loosening of prostheses and inflammatory osteolysis; therefore, disruption of osteoclastogenesis is considered a crucial treatment option for these issues. WKYMVm, a synthetic peptide, which is a potent FPR2 agonist, exerts an immunoregulatory effect. This peptide inhibits the production of inflammatory cytokines, such as (IL)‐1β and TNF‐α, thus regulating inflammation. However, there are only few reports on the role of WKYMVm and FPR2 in osteoclast cytology. In the current study, we found that WKYMVm negatively regulates RANKL‐ and lipopolysaccharide (LPS)‐induced osteoclast differentiation and maturation in vitro and alleviates LPS‐induced osteolysis in animal models. WKYMVm down‐regulated the expression of osteoclast marker genes and resorption activity. Furthermore, WKYMVm inhibited osteoclastogenesis directly through reducing the phosphorylation of STAT3 and NF‐kB and indirectly through the CD9/gp130/STAT3 pathway. In conclusion, our findings demonstrated the potential medicinal value of WKYMVm for the treatment of inflammatory osteolysis.

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“…Biased signaling is widespread in the chemokine system, with different chemokine ligands eliciting unique signaling profiles at the same receptor . While much less established, biased signaling may also play a role in the formylated peptide receptor system . Although biased signaling has not been explicitly described in D. discoideum , D. discoideum nevertheless has numerous cytosolic effectors available to initiate complex signaling outcomes that are adaptable in different environmental circumstances .…”

Section: How Much Information?mentioning

confidence: 99%

“…106 While much less established, biased signaling may also play a role in the formylated peptide receptor system. 98,99,[135][136][137] Although biased signaling has not been explicitly 139 Importantly, other recent studies suggest that differences in chemokine-receptor interactions far from the traditional receptor binding pocket influence how a single receptor can mediate alternative functional responses. 140,141 In one example, CXCL12 provokes and arrests chemotaxis in a monomeric and dimeric form, respectively, and structures of CXCL12 bound to its receptor CXCR4 in both forms demonstrate mutually exclusive interactions that may influence CXCL12's opposing effects on chemotaxis.…”

Section: Understanding Chemotactic Information By Transmitter Capacitymentioning

confidence: 99%

Decoding the chemotactic signal

Thomas

Kleist

Volkman

2018

Journal of Leukocyte Biology

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From an individual bacterium to the cells that compose the human immune system, cellular chemotaxis plays a fundamental role in allowing cells to navigate, interpret, and respond to their environments. While many features of cellular chemotaxis are shared among systems as diverse as bacteria and human immune cells, the machinery that guides the migration of these model organisms varies widely. In this article, we review current literature on the diversity of chemoattractant ligands, the cell surface receptors that detect and process chemotactic gradients, and the link between signal recognition and the regulation of cellular machinery that allow for efficient directed cellular movement. These facets of cellular chemotaxis are compared among E. coli, Dictyostelium discoideum, and mammalian neutrophils to derive organizational principles by which diverse cell systems sense and respond to chemotactic gradients to initiate cellular migration.

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FPR2 signaling without β-arrestin recruitment alters the functional repertoire of neutrophils

Cited by 49 publications

References 42 publications

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

Decoding the chemotactic signal

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