scholarly journals Annexin A1 attenuates neutrophil migration and IL-6 expression through Fpr2 in a mouse model of Streptococcus suis-induced meningitis

2020 ◽  
pp. IAI.00680-20
Author(s):  
Chengpei Ni ◽  
Song Gao ◽  
Yuling Zheng ◽  
Peng Liu ◽  
Yajie Zhai ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Mediator ◽  
Therapeutic Option ◽  
Neutrophil Migration ◽  
Streptococcus Suis ◽  
Formyl Peptide Receptor ◽  
Annexin A1 ◽  
Formyl Peptide ◽  
Anti Inflammatory

Streptococcus suis (S. suis) serotype 2 is a crucial pathogenic cause of bacterial meningitis, a life-threatening disease with neurological sequelae and high rates of mortality. Inflammation triggered by S. suis infection must be precisely regulated to prevent further tissue damage. As a glucocorticoid anti-inflammatory mediator, Annexin A1 (AnxA1) mainly acts through formyl peptide receptor 2 (Fpr2) to alleviate inflammation in the peripheral system. In this research, we evaluated the roles of AnxA1 and Fpr2 in a mouse model of S. suis meningitis created via intracisternal infection in Fpr2-deficient (Fpr2−/−) and wild-type (WT) mice. We revealed that Fpr2−/− mice were highly susceptible to S. suis meningitis, displaying increased inflammatory cytokine levels, bacterial dissemination, and neutrophil migration compared with the findings in WT mice. Additionally, AnxA1 exerted anti-inflammatory effects through Fpr2, such as attenuation of leukocyte infiltration, inflammatory mediator production, and astrocyte or microglial activation in the brain. Importantly, we found that the anti-migratory function of AnxA1 decreases neutrophil adherence to the endothelium through Fpr2. Finally, an in vitro study revealed that AnxA1 potentially suppresses IL-6 expression through the Fpr2/p38/COX-2 pathway. These data demonstrated that Fpr2 is an anti-inflammatory receptor that regulates neutrophil migration in mice with S. suis meningitis and identified AnxA1 as a potential therapeutic option.

Design and characterization of a cleavage-resistant Annexin A1 mutant to control inflammation in the microvasculature

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4288-4296 ◽  
Author(s):  
Magali Pederzoli-Ribeil ◽  
Francesco Maione ◽  
Dianne Cooper ◽  
Adam Al-Kashi ◽  
Jesmond Dalli ◽  
...  
Keyword(s):  
Polymorphonuclear Leukocytes ◽  
Early Stage ◽  
Leukocyte Adhesion ◽  
Formyl Peptide Receptor ◽  
Annexin A1 ◽  
Formyl Peptide ◽  
Anti Inflammatory ◽  
Human Polymorphonuclear Leukocytes

Abstract Human polymorphonuclear leukocytes adhesion to endothelial cells during the early stage of inflammation leads to cell surface externalization of Annexin A1 (AnxA1), an effector of endogenous anti-inflammation. The antiadhesive properties of AnxA1 become operative to finely tune polymorphonuclear leukocytes transmigration to the site of inflammation. Membrane bound proteinase 3 (PR3) plays a key role in this microenvironment by cleaving the N terminus bioactive domain of AnxA1. In the present study, we generated a PR3-resistant human recombinant AnxA1—named superAnxA1 (SAnxA1)—and tested its in vitro and in vivo properties in comparison to the parental protein. SAnxA1 bound and activated formyl peptide receptor 2 in a similar way as the parental protein, while showing a resistance to cleavage by recombinant PR3. SAnxA1 retained anti-inflammatory activities in the murine inflamed microcirculation (leukocyte adhesion being the readout) and in skin trafficking model. When longer-lasting models of inflammation were applied, SAnxA1 displayed stronger anti-inflammatory effect over time compared with the parental protein. Together these results indicate that AnxA1 cleavage is an important process during neutrophilic inflammation and that controlling the balance between AnxA1/PR3 activities might represent a promising avenue for the discovery of novel therapeutic approaches.

scholarly journals The formyl peptide receptor agonist Ac2-26 alleviates neuroinflammation in a mouse model of pneumococcal meningitis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Marvin Rüger ◽  
Eugenia Kipp ◽  
Nadine Schubert ◽  
Nicole Schröder ◽  
Thomas Pufe ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Bacterial Meningitis ◽  
Mouse Model ◽  
Post Infection ◽  
Pneumococcal Meningitis ◽  
Hippocampal Formation ◽  
Formyl Peptide Receptor ◽  
Formyl Peptide ◽  
Anti Inflammatory ◽  
Deficient Mice

Abstract Background Bacterial meningitis is still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein-coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands, including pro- and anti-inflammatory ones. Here, we investigated the effects of the annexin A1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis. Methods Wildtype (WT) and Fpr1- and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8, and 24 h post-infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR) 30 h post-infection. Results Ac2-26-treated WT mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glial cell responses in the hippocampal formation and cortex. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice. Irrespective of Ac2-26 treatment, inflammation was more severe in Fpr2-deficient compared to Fpr1-deficient mice. Conclusions In summary, this study demonstrates anti-inflammatory properties of Ac2-26 in a model of bacterial meningitis, which are mediated via FPR2, but not FPR1. Ac2-26 and other FPR2 modulators might be promising targets for the development of novel therapies for Streptococcus pneumoniae-induced meningitis.

scholarly journals Annexin A1 Mimetic Peptide and Piperlongumine: Anti-Inflammatory Profiles in Endotoxin-Induced Uveitis

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3170
Author(s):  
Ana Paula Girol ◽  
Caroline de Freitas Zanon ◽  
Ícaro Putinhon Caruso ◽  
Sara de Souza Costa ◽  
Helena Ribeiro Souza ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Mononuclear Cells ◽  
Formyl Peptide Receptor ◽  
Annexin A1 ◽  
Protective Effects ◽  
Mimetic Peptide ◽  
Formyl Peptide ◽  
Leukocyte Influx ◽  
Cox 2 ◽  
Anti Inflammatory

Uveitis is one of the main causes of blindness worldwide, and therapeutic alternatives are worthy of study. We investigated the effects of piperlongumine (PL) and/or annexin A1 (AnxA1) mimetic peptide Ac2-26 on endotoxin-induced uveitis (EIU). Rats were inoculated with lipopolysaccharide (LPS) and intraperitoneally treated with Ac2-26 (200 µg), PL (200 and 400 µg), or Ac2-26 + PL after 15 min. Then, 24 h after LPS inoculation, leukocytes in aqueous humor, mononuclear cells, AnxA1, formyl peptide receptor (fpr)1, fpr2, and cyclooxygenase (COX)-2 were evaluated in the ocular tissues, along with inflammatory mediators in the blood and macerated supernatant. Decreased leukocyte influx, levels of inflammatory mediators, and COX-2 expression confirmed the anti-inflammatory actions of the peptide and pointed to the protective effects of PL at higher dosage. However, when PL and Ac2-26 were administered in combination, the inflammatory potential was lost. AnxA1 expression was elevated among groups treated with PL or Ac2-26 + PL but reduced after treatment with Ac2-26. Fpr2 expression was increased only in untreated EIU and Ac2-26 groups. The interaction between Ac2-26 and PL negatively affected the anti-inflammatory action of Ac2-26 or PL. We emphasize that the anti-inflammatory effects of PL can be used as a therapeutic strategy to protect against uveitis.

Electroacupuncture promotes microglial M2 polarization in ischemic stroke via annexin A1

2021 ◽  
pp. 096452842110575
Author(s):  
Jing Zou ◽  
Guo-fu Huang ◽  
Qian Xia ◽  
Xing Li ◽  
Jing Shi ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Mouse Model ◽  
Inflammatory Cytokines ◽  
Infarct Volume ◽  
Formyl Peptide Receptor ◽  
Annexin A1 ◽  
Protective Effects ◽  
Arginase 1 ◽  
M2 Polarization ◽  
Anti Inflammatory

Background: Neuroinflammation is the leading cause of neurological sequelae in ischemic stroke. Recently, we reported that the anti-inflammatory mediator annexin A1 (ANXA1) favored microglial M2 polarization in brain injury. The purpose of this study was to investigate electroacupuncture (EA) treatment and its potentially ANXA1-mediated anti-inflammatory effects in the middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model of stroke. Methods: Treatment with EA consisted of dense-sparse frequencies (alternating 4 Hz sparse waves for 1.5 s and 16 Hz dense waves for 1.5 s) at CV24 and GV26. Intracerebroventricular (ICV) injection of Boc-2 (5 µM) or short hairpin RNA (sh)ANXA1 (2 µL) 3 days before EA was performed to block the effects of ANXA1. Results: EA pretreatment enhanced expression of ANXA1 and its receptor, formyl peptide receptor (FPR), when compared to MCAO/R alone. EA treatment also rescued MCAO/R-induced deficits in neurological performance, and learning and memory, and reduced infarct volume. Double immunofluorescent labeling showed that EA prevented MCAO/R-induced changes in microglial activation and morphology. EA also reduced the release of pro-inflammatory cytokines, such as interleukin (IL)-1β, inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)-α, while increasing the release of anti-inflammatory cytokines, such as arginase-1 (Arg-1) and brain-derived neurotrophic factor (BDNF). All EA-induced effects were either partially or completely prevented by prior administration of FPR antagonist Boc-2 or shANXA1. Conclusion: The current study provides strong evidence that EA treatment has protective effects against ischemic stroke in the MCAO/R mouse model and that the mechanism likely involves the promotion of M2 polarization in microglia via ANXA1.

scholarly journals Annexin A1/Formyl Peptide Receptor Pathway Controls Uterine Receptivity to the Blastocyst

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1188 ◽  
Author(s):  
Cristina B. Hebeda ◽  
Silvana Sandri ◽  
Cláudia M. Benis ◽  
Marina de Paula-Silva ◽  
Rodrigo A. Loiola ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Embryo Implantation ◽  
Formyl Peptide Receptor ◽  
Annexin A1 ◽  
Uterine Receptivity ◽  
Mucin 1 ◽  
Human Trophoblast ◽  
Junction Molecules ◽  
Formyl Peptide

Embryo implantation into the uterine wall is a highly modulated, complex process. We previously demonstrated that Annexin A1 (AnxA1), which is a protein secreted by epithelial and inflammatory cells in the uterine microenvironment, controls embryo implantation in vivo. Here, we decipher the effects of recombinant AnxA1 in this phenomenon by using human trophoblast cell (BeWo) spheroids and uterine epithelial cells (Ishikawa; IK). AnxA1-treated IK cells demonstrated greater levels of spheroid adherence and upregulation of the tight junction molecules claudin-1 and zona occludens-1, as well as the glycoprotein mucin-1 (Muc-1). The latter effect of AnxA1 was not mediated through IL-6 secreted from IK cells, a known inducer of Muc-1 expression. Rather, these effects of AnxA1 involved activation of the formyl peptide receptors FPR1 and FPR2, as pharmacological blockade of FPR1 or FPR1/FPR2 abrogated such responses. The downstream actions of AnxA1 were mediated through the ERK1/2 phosphorylation pathway and F-actin polymerization in IK cells, as blockade of ERK1/2 phosphorylation reversed AnxA1-induced Muc-1 and claudin-1 expression. Moreover, FPR2 activation by AnxA1 induced vascular endothelial growth factor (VEGF) secretion by IK cells, and the supernatant of AnxA1-treated IK cells evoked angiogenesis in vitro. In conclusion, these data highlight the role of the AnxA1/FPR1/FPR2 pathway in uterine epithelial control of blastocyst implantation.

scholarly journals Annexin A1 protects against cerebral ischemia–reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xin Xu ◽  
Weiwei Gao ◽  
Lei Li ◽  
Jiheng Hao ◽  
Bin Yang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Mouse Model ◽  
Clinical Outcomes ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Mtor Pathway ◽  
Annexin A1 ◽  
Cerebral Ischemia Reperfusion ◽  
Anti Inflammatory

Abstract Background Cerebral ischemia–reperfusion (I/R) injury is a major cause of early complications and unfavorable outcomes after endovascular thrombectomy (EVT) therapy in patients with acute ischemic stroke (AIS). Recent studies indicate that modulating microglia/macrophage polarization and subsequent inflammatory response may be a potential adjunct therapy to recanalization. Annexin A1 (ANXA1) exerts potent anti-inflammatory and pro-resolving properties in models of cerebral I/R injury. However, whether ANXA1 modulates post-I/R-induced microglia/macrophage polarization has not yet been fully elucidated. Methods We retrospectively collected blood samples from AIS patients who underwent successful recanalization by EVT and analyzed ANXA1 levels longitudinally before and after EVT and correlation between ANXA1 levels and 3-month clinical outcomes. We also established a C57BL/6J mouse model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R) and an in vitro model of oxygen–glucose deprivation and reoxygenation (OGD/R) in BV2 microglia and HT22 neurons to explore the role of Ac2-26, a pharmacophore N-terminal peptide of ANXA1, in regulating the I/R-induced microglia/macrophage activation and polarization. Results The baseline levels of ANXA1 pre-EVT were significantly lower in 23 AIS patients, as compared with those of healthy controls. They were significantly increased to the levels found in controls 2–3 days post-EVT. The increased post-EVT levels of ANXA1 were positively correlated with 3-month clinical outcomes. In the mouse model, we then found that Ac2-26 administered at the start of reperfusion shifted microglia/macrophage polarization toward anti-inflammatory M2-phenotype in ischemic penumbra, thus alleviating blood–brain barrier leakage and neuronal apoptosis and improving outcomes at 3 days post-tMCAO/R. The protection was abrogated when mice received Ac2-26 together with WRW4, which is a specific antagonist of formyl peptide receptor type 2/lipoxin A4 receptor (FPR2/ALX). Furthermore, the interaction between Ac2-26 and FPR2/ALX receptor activated the 5’ adenosine monophosphate-activated protein kinase (AMPK) and inhibited the downstream mammalian target of rapamycin (mTOR). These in vivo findings were validated through in vitro experiments. Conclusions Ac2-26 modulates microglial/macrophage polarization and alleviates subsequent cerebral inflammation by regulating the FPR2/ALX-dependent AMPK-mTOR pathway. It may be investigated as an adjunct strategy for clinical prevention and treatment of cerebral I/R injury after recanalization. Plasma ANXA1 may be a potential biomarker for outcomes of AIS patients receiving EVT.

scholarly journals Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rishi Man Chugh ◽  
Hang-soo Park ◽  
Abdeljabar El Andaloussi ◽  
Amro Elsharoud ◽  
Sahar Esfandyari ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Therapeutic Option ◽  
Interleukin 10 ◽  
Reproductive Age ◽  
Mesenchymal Stem Cell Therapy ◽  
Anti Inflammatory

Abstract Background Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human bone marrow mesenchymal stem cells (BM-hMSC) and their secreted factors (secretome) exhibit robust anti-inflammatory capabilities in various biological systems. We evaluated the therapeutic efficacy of BM-hMSC and its secretome in both in vitro and in vivo PCOS models. Methods For in vitro experiment, we treated conditioned media from BM-hMSC to androgen-producing H293R cells and analyzed androgen-producing gene expression. For in vivo experiment, BM-hMSC were implanted into letrozole (LTZ)-induced PCOS mouse model. BM-hMSC effect in androgen-producing cells or PCOS model mice was assessed by monitoring cell proliferation (immunohistochemistry), steroidogenic gene expression (quantitative real-time polymerase chain reaction [qRT-PCR] and Western blot, animal tissue assay (H&E staining), and fertility by pup delivery. Results BM-hMSC significantly downregulate steroidogenic gene expression, curb inflammation, and restore fertility in treated PCOS animals. The anti-inflammatory cytokine interleukin-10 (IL-10) played a key role in mediating the effects of BM-hMSC in our PCOS models. We demonstrated that BM-hMSC treatment was improved in metabolic and reproductive markers in our PCOS model and able to restore fertility. Conclusion Our study demonstrates for the first time the efficacy of intra-ovarian injection of BM-hMSC or its secretome to treat PCOS-related phenotypes, including both metabolic and reproductive dysfunction. This approach may represent a novel therapeutic option for women with PCOS. Our results suggest that BM-hMSC can reverse PCOS-induced inflammation through IL-10 secretion. BM-hMSC might be a novel and robust therapeutic approach for PCOS treatment.

Alterations in the profile of blood neutrophil membrane receptors caused by in vivo adrenocorticotrophic hormone actions

2014 ◽  
Vol 307 (9) ◽  
pp. E754-E763 ◽  
Author(s):  
Isabel Daufenback Machado ◽  
José Roberto Santin ◽  
Carine Cristiane Drewes ◽  
Cristiane Damas Gil ◽  
Sonia Maria Oliani ◽  
...  
Keyword(s):  
Neutrophil Migration ◽  
Receptor Activation ◽  
Peritoneal Macrophages ◽  
Membrane Receptors ◽  
Formyl Peptide Receptor ◽  
Adrenocorticotrophic Hormone ◽  
Blood Neutrophil ◽  
Formyl Peptide

Elevated levels of adrenocorticotrophic hormone (ACTH) mobilize granulocytes from bone marrow into the blood, although these neutrophils are refractory to a full migratory response into inflamed tissues. Here, we investigated the dependence of glucocorticoid receptor activation and glucocorticoid-regulated protein annexin A1 (ANXA1) on ACTH-induced neutrophilia and the phenotype of blood neutrophil after ACTH injection, focusing on adhesion molecule expressions and locomotion properties. ACTH injection (5 μg ip, 4 h) induced neutrophilia in wild-type (WT) mice and did not alter the elevated numbers of neutrophils in RU-38486 (RU)-pretreated or ANXA1−/− mice injected with ACTH. Neutrophils from WT ACTH-treated mice presented higher expression of Ly6G+ANXA1high, CD18high, CD62Lhigh, CD49high, CXCR4high, and formyl-peptide receptor 1 (FPR1low) than those observed in RU-pretreated or ANXA1−/− mice. The membrane phenotype of neutrophils collected from WT ACTH-treated mice was paralleled by elevated fractions of rolling and adherent leukocytes to the cremaster postcapillary venules together with impaired neutrophil migration into inflamed air pouches in vivo and in vitro reduced formyl-methionyl-leucyl-phenylalanine (fMLP) or stromal-derived factor-1 (SDF-1α)-induced chemotaxis. In an 18-h senescence protocol, neutrophils from WT ACTH-treated mice had a higher proportion of ANXAVlow/CXCR4low, and they were less phagocytosed by peritoneal macrophages. We conclude that alterations on HPA axis affect the pattern of membrane receptors in circulating neutrophils, which may lead to different neutrophil phenotypes in the blood. Moreover, ACTH actions render circulating neutrophils to a phenotype with early reactivity, such as in vivo leukocyte-endothelial interactions, but with impaired locomotion and clearance.

scholarly journals Antiflammin-2 Activates the Human Formyl-Peptide Receptor Like 1

2006 ◽  
Vol 6 ◽  
pp. 1375-1384 ◽  
Author(s):  
Ahmad M. Kamal ◽  
Richard P.G. Hayhoe ◽  
Anbalakan Paramasivam ◽  
Dianne Cooper ◽  
Roderick J. Flower ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Inhibitory Effect ◽  
Formyl Peptide Receptor ◽  
Annexin A1 ◽  
Hek 293 ◽  
Peptide Receptor ◽  
293 Cells ◽  
Formyl Peptide ◽  
Anti Inflammatory ◽  
Extracellular Regulated Kinase

The anti-inflammatory actions of the nonapeptide antiflammin-2, identified by homology with uteroglobin and annexin-A1 sequences, have been described in some detail, yet its mechanisms of action remain elusive. Since recent data indicate an involvement of the formyl peptide receptor (FPR)-like 1 (or FPRL-1) in the effects of annexin-A1, we have tested here the effect of antiflammin-2 with respect to this receptor family. Using HEK-293 cells expressing either human FPR and FPRL-1, and an annexin-A1 peptide as tracer ([125I-Tyr]-Ac2-26), we found that antiflammin-2 competed for binding only at FPRL-1, and not FPR, with an approximate EC50of 1 μM. In line with data produced for the full-length protein, genuine receptor activation by antiflammin-2 was confirmed by rapid phosphorylation of extracellular-regulated kinase 1 and 2. Finally, study of the neutrophil interaction with activated endothelium under flow demonstrated an inhibitory effect of antiflammin-2, thus providing functional support to a role for the antiflammin-2/FPRL-1 anti-inflammatory axis.

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

2019 ◽  
Author(s):  
Simon Lind ◽  
Martina Sundqvist ◽  
Rikard Holmdahl ◽  
Claes Dahlgren ◽  
Huamei Forsman ◽  
...  
Keyword(s):  
Human Subjects ◽  
Formyl Peptide Receptor ◽  
Healthy Human ◽  
Formyl Peptide ◽  
Blood Neutrophils ◽  
Small Molecule Compound ◽  
Anti Inflammatory ◽  
Future Utility

AbstractDespite 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 Ca2+ 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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