Barbadin selectively modulates FPR2-mediated neutrophil functions independent of receptor endocytosis

Sundqvist, Martina; Holdfeldt, André; Wright, Shane C.; Møller, Thor C.; Siaw, Esther; Jennbacken, Karin; Franzyk, Henrik; Bouvier, Michel; Dahlgren, Cláes; Forsman, Huamei

doi:10.1101/2020.04.30.070011

Cited by 4 publications

(4 citation statements)

References 41 publications

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“…On the other hand, modifying the chemotaxis of neutrophils by regulating the internalization of GPCRs may improve the inflammatory response in the lungs during sepsis. Barbadin is a novel inhibitor that blocks the interaction of β-arrestin and AP-2, reducing receptor desensitization by inhibiting clathrin-mediated internalization of GPCRs, thus allowing neutrophils to continuously respond to external stimuli ( 325 , 326 ). Furthermore, LMBD1, the first protein was shown to be involved in the regulation of insulin receptor (IR) internalization ( 327 ), is hypothesized to contain nine transmembrane domains that subcellular localize in multiple membrane-bound organelles, including lysosomes and plasma membranes ( 328 ).…”

Section: Potential Therapeutic Targets For Septic Ardsmentioning

confidence: 99%

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

Wang

Zhu²,

Liu³

et al. 2023

Front. Immunol.

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Sepsis is defined as a life-threatening dysfunction due to a dysregulated host response to infection. It is a common and complex syndrome and is the leading cause of death in intensive care units. The lungs are most vulnerable to the challenge of sepsis, and the incidence of respiratory dysfunction has been reported to be up to 70%, in which neutrophils play a major role. Neutrophils are the first line of defense against infection, and they are regarded as the most responsive cells in sepsis. Normally, neutrophils recognize chemokines including the bacterial product N-formyl-methionyl-leucyl-phenylalanine (fMLP), complement 5a (C5a), and lipid molecules Leukotriene B4 (LTB4) and C-X-C motif chemokine ligand 8 (CXCL8), and enter the site of infection through mobilization, rolling, adhesion, migration, and chemotaxis. However, numerous studies have confirmed that despite the high levels of chemokines in septic patients and mice at the site of infection, the neutrophils cannot migrate to the proper target location, but instead they accumulate in the lungs, releasing histones, DNA, and proteases that mediate tissue damage and induce acute respiratory distress syndrome (ARDS). This is closely related to impaired neutrophil migration in sepsis, but the mechanism involved is still unclear. Many studies have shown that chemokine receptor dysregulation is an important cause of impaired neutrophil migration, and the vast majority of these chemokine receptors belong to the G protein-coupled receptors (GPCRs). In this review, we summarize the signaling pathways by which neutrophil GPCR regulates chemotaxis and the mechanisms by which abnormal GPCR function in sepsis leads to impaired neutrophil chemotaxis, which can further cause ARDS. Several potential targets for intervention are proposed to improve neutrophil chemotaxis, and we hope that this review may provide insights for clinical practitioners.

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Section: Potential Therapeutic Targets For Septic Ardsmentioning

confidence: 99%

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

Wang

Zhu²,

Liu³

et al. 2023

Front. Immunol.

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“…showed that the receptor down-stream signals generated by GPR84 reactivate FPR2 desensitized neutrophils also with this agonist which suggests that the reactivating signal(s) are generated independent of β-arrestin recruitment. The fact that also neutrophils activated/desensitized with FPR2 agonists unable to recruit β-arrestin (e.g., F2Pal10 and PSMα2) are reactivated by the receptor cross-talk signals generated by GPR84 (this study) as well as by the PAFR and P2Y2R (16)(17)(18)35), show that β-arrestin is not at all involved in the receptor cross-talk reactivation of FPR2. It would be highly interesting to explore the effect on neutrophil activation of a biased GPR84 agonist that is in favor of β-arrestin recruitment but to our knowledge, such a biased agonist has not yet been identified.…”

Section: Discussionmentioning

confidence: 66%

“…Recent research show that the signals generated by agonist occupied GPCRs differ depending on the agonist that initiates signaling, of which some, in addition to activating the heterotrimeric G protein, also may recruit β-arrestin to initiate non-canonical signaling (33). The FPR2 agonist F2Pal10 activates a Gi containing G-proteins but lacks the ability to recruit β-arrestin, and the signals downstream the activated receptor is thus biased (18,34,35). The data obtained using F2Pal10 as an FPR2 desensitizing agent clearly show that β-arrestin recruitment downstream FPR2 is not a feature that is required for the amplification the of GPR84 response.…”

Section: The Fpr2 Reactivation Signals Are Sensitive To Calyculin a Amentioning

confidence: 99%

The two formyl peptide receptors differently regulate GPR84-mediated neutrophil NADPH-oxidase activity

Mårtensson

Sundqvist

Manandhar

et al. 2020

Preprint

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Neutrophils express many G protein-coupled receptors (GPCRs) including the two formyl peptide receptors (FPR1 and FPR2) and the medium chain fatty acid receptor GPR84. The FPRs are known to define a hierarchy among neutrophil GPCRs, i.e., the GPCR-mediated response can be either suppressed or amplified by signals generated by FPRs. In this study, we investigated the position of GPR84 in the FPR-defined hierarchy regarding the activation of neutrophil NADPH-oxidase, an enzyme system designed to generate reactive oxygen species (ROS). When naïve neutrophils are activated by GPR84 agonists a modest ROS release was induced. However, vast amounts of ROS production was induced by these GPR84 agonists in FPR2-desensitized neutrophils, and the response is inhibited not only by a GPR84 antagonist but also by an FPR2 specific antagonist. This suggests that the amplified GPR84 agonist response is achieved through a reactivation of the desensitized FPR2. In addition, the GPR84-mediated FPR2 reactivation was independent of β-arrestin recruitment and sensitive to a protein phosphatase inhibitor. In contrast, the modest ROS production induced by GPR84 agonists was primarily suppressed in FPR1-desensitized neutrophils through hierarchical desensitization of GPR84 by FPR1 generated signals.In summary, our data show that FPRs control the NADPH-oxidase activity mediated through GPR84 in human neutrophils. While an amplified ROS generation is achieved by GPR84 agonists through reactivation of desensitized FPR2, FPR1 heterologously desensitizes GPR84 and by that suppresses the release of ROS induced by GPR84 agonists.

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“…Other FPR2 agonists, structurally unrelated to PSMα2, have earlier been shown to trigger a biased signaling/functional selective response (20,21,30,43). The concept of biased signaling applies also to FPR1 as illustrated by the results presented in a recent study, showing that signaling induced by the novel FPR1-selective small-molecule agonist RE-04-001 was strongly biased toward the PLC-PIP2-Ca 2+ and the ERK1/2 activation pathways, but away from β-arrestin recruitment (44).…”

Section: Discussionmentioning

confidence: 99%

Structural determinants in the Staphylococcus aureus derived phenol-soluble modulin α2 peptide required for neutrophil formyl peptide receptor activation

Viklund

Fredriksson

Holdfeldt

et al. 2021

Preprint

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Highly pathogenic Staphylococcus aureus strains produce phenol-soluble modulins (PSMs), peptides which are formylated N-terminally. Nanomolar concentrations of PSMα2 are recognized by formyl peptide receptor 2 (FPR2), but unlike the prototypic FPR2 agonist WKYMVM, PSMα2 is a biased signaling agonist. A shortened N-terminal PSMα2 variant, consisting of the five N- terminal residues, is selectively recognized by the closely related FPR1, showing that the C- terminal part of PSMα2 confers FPR2 selectivity, while the N-terminal part may interact with the FPR1 binding site. In the present study, a combined pharmacological and genetic approach, involving primary neutrophils and engineered FPR “knock-in” and “knock-out” cells, was used to gain molecular insights into FPR1 and FPR2 recognition of formyl peptides and the receptor downstream signaling induced by these peptides. In comparison to the full-length PSMα2, we show that the peptide in which the N-terminal part of PSMα2 was replaced by fMIFL (an FPR1- selective peptide agonist) potently activates both FPRs for production of superoxide anions and β- arrestin recruitment. A shortened analogue of PSMα2 (PSMα21-12), lacking the nine C-terminal residues activated both FPR1 and FPR2 to produce ROS, whereas β-arrestin recruitment was only mediated through FPR1. However, a single amino acid replacement (Gly-2 to Ile-2) in PSMα21-12 was sufficient to alter FPR2 signaling to include β-arrestin recruitment, highlighting a key role of Gly-2 in conferring FPR2 biased signaling. In conclusion, we provide novel structural insights into FPR1 and FPR2 recognition as well as the signaling induced by interaction with formyl peptides derived from PSMα2, originating from Staphylococcus aureus bacteria.

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Barbadin selectively modulates FPR2-mediated neutrophil functions independent of receptor endocytosis

Cited by 4 publications

References 41 publications

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

The role of G protein-coupled receptor in neutrophil dysfunction during sepsis-induced acute respiratory distress syndrome

The two formyl peptide receptors differently regulate GPR84-mediated neutrophil NADPH-oxidase activity

Structural determinants in the Staphylococcus aureus derived phenol-soluble modulin α2 peptide required for neutrophil formyl peptide receptor activation

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