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 Mitocryptide-2: Identification of Its Minimum Structure for Specific Activation of FPR2–Possible Receptor Switching from FPR2 to FPR1 by Its Physiological C-terminal Cleavages

2021 ◽  
Vol 22 (8) ◽  
pp. 4084
Author(s):  
Takayuki Marutani ◽  
Kodai Nishino ◽  
Tomoyuki Miyaji ◽  
Keisuke Kamada ◽  
Koji Ohura ◽  
...  
Keyword(s):  
Critical Factor ◽  
Formyl Peptide Receptor ◽  
Amino Acid Residues ◽  
Hek 293 ◽  
Peptide Receptor ◽  
Chemical Structures ◽  
C Terminus ◽  
293 Cells ◽  
Mitochondrial Cytochrome B ◽  
Formyl Peptide

Mitocryptides are a novel family of endogenous neutrophil-activating peptides originating from various mitochondrial proteins. Mitocryptide-2 (MCT-2) is one of such neutrophil-activating peptides, and is produced as an N-formylated pentadecapeptide from mitochondrial cytochrome b. Although MCT-2 is a specific endogenous ligand for formyl peptide receptor 2 (FPR2), the chemical structure within MCT-2 that is responsible for FPR2 activation is still obscure. Here, we demonstrate that the N-terminal heptapeptide structure of MCT-2 with an N-formyl group is the minimum structure that specifically activates FPR2. Moreover, the receptor molecule for MCT-2 is suggested to be shifted from FPR2 to its homolog formyl peptide receptor 1 (FPR1) by the physiological cleavages of its C-terminus. Indeed, N-terminal derivatives of MCT-2 with seven amino acid residues or longer caused an increase of intracellular free Ca2+ concentration in HEK-293 cells expressing FPR2, but not in those expressing FPR1. Those MCT-2 derivatives also induced β-hexosaminidase secretion in neutrophilic/granulocytic differentiated HL-60 cells via FPR2 activation. In contrast, MCT-2(1–4), an N-terminal tetrapeptide of MCT-2, specifically activated FPR1 to promote those functions. Moreover, MCT-2 was degraded in serum to produce MCT-2(1–4) over time. These findings suggest that MCT-2 is a novel critical factor that not only initiates innate immunity via the specific activation of FPR2, but also promotes delayed responses by the activation of FPR1, which may include resolution and tissue regeneration. The present results also strongly support the necessity of considering the exact chemical structures of activating factors for the investigation of innate immune responses.

Abstract P217: Mitochondrial N-Formyl Peptides Elicit Changes in Endothelial Cell Cytoskeleton via Formyl Peptide Receptor Activation

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Camilla F Wenceslau ◽  
Cameron G McCarthy ◽  
R.Clinton Webb
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vascular Dysfunction ◽  
Receptor Activation ◽  
Vascular Leakage ◽  
Formyl Peptide Receptor ◽  
Experimental Hypertension ◽  
Peptide Receptor ◽  
Formyl Peptide ◽  
Formyl Peptides

One major pathophysiological characteristic of cardiovascular disease, including hypertension, is vascular dysfunction. Recently, we demonstrated that mitochondrial damage-associated molecular patterns are elevated in the circulation of SHR. Mitochondria carry hallmarks of their bacterial ancestry and one of these hallmarks is that this organelle still uses an N-formyl-methionyl-tRNA as an initiator of protein synthesis. We observed that mitochondrial N-formyl peptides (F-MIT) infusion into rats induces inflammation and vascular dysfunction, including vascular leakage, via formyl peptide receptor (FPR) activation. However, neutrophil depletion did not change this response. Therefore, we hypothesize that F-MIT via FPR activation elicits changes directly to cytoskeleton-regulating proteins in vascular cells, which may lead to increased vascular permeability. To test this hypothesis we used vascular smooth muscle cells (VSMC) and endothelial cells harvested from aortas of Sprague-Dawley rats (n=5) and human donors (n=5), respectively. Cells were divided into three groups for Western blot analysis of cytoskeleton-regulating proteins. The cells were incubated for 20 minutes in medium with either vehicle (non-formylated peptide), F-MIT (10 μM), or F-MIT after a 5-minute pre-incubation with FPR1 and 2 antagonists (Cyclosporine H, CsH, 1 μM and WRW4, 10 μM). In endothelial cells, the treatment with F-MIT increased the protein expression of RhoA/ROCK (Rho: 1.8 fold vs. Veh; ROCK: 1.4 fold vs. Veh, p<0.05), cell division control protein 42 (CDC42) (2.0 fold vs. Veh, p<0.05) and phospho-myosin light chain (MLC) Thr/Ser19 (1.5 fold vs. Veh, p<0.05). These changes were all abolished in the presence of FPR antagonists. On the other hand, F-MIT decreased expression of phospho-MLC (0.6 fold vs. Veh, p<0.05) and CDC42 (0.5 fold vs. Veh, p<0.05) and did not change RhoA/ROCK expression in VSMC. In conclusion, F-MIT, via FPR activation, elicits direct changes in endothelial cell and VSMC cytoskeleton-regulating proteins. This interaction can lead to endothelial contraction, increased vascular leakage and attenuated barrier function as observed in clinical and experimental hypertension.

Annexin A1 and the formyl peptide receptor family: neuroendocrine and metabolic aspects

2008 ◽  
Vol 8 (6) ◽  
pp. 765-776 ◽  
Author(s):  
C JOHN ◽  
F GAVINS ◽  
N BUSS ◽  
P COVER ◽  
J BUCKINGHAM
Keyword(s):  
Formyl Peptide Receptor ◽  
Annexin A1 ◽  
Peptide Receptor ◽  
Formyl Peptide ◽  
Receptor Family

Dual modulation of formyl peptide receptor 2 by aspirin‐triggered lipoxin contributes to its anti‐inflammatory activity

2020 ◽  
Vol 34 (5) ◽  
pp. 6920-6933 ◽  
Author(s):  
Yunjun Ge ◽  
Shuo Zhang ◽  
Junlin Wang ◽  
Fangbo Xia ◽  
Jian‐Bo Wan ◽  
...  
Keyword(s):  
Inflammatory Activity ◽  
Formyl Peptide Receptor ◽  
Peptide Receptor ◽  
Formyl Peptide ◽  
Anti Inflammatory

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 Proresolving and Tissue-Protective Actions of Annexin A1–Based Cleavage-Resistant Peptides Are Mediated by Formyl Peptide Receptor 2/Lipoxin A4 Receptor

2013 ◽  
Vol 190 (12) ◽  
pp. 6478-6487 ◽  
Author(s):  
Jesmond Dalli ◽  
Angelo P. Consalvo ◽  
Vicki Ray ◽  
Clara Di Filippo ◽  
Michele D’Amico ◽  
...  
Keyword(s):  
Formyl Peptide Receptor ◽  
Annexin A1 ◽  
Lipoxin A4 ◽  
Peptide Receptor ◽  
Protective Actions ◽  
Formyl Peptide
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