A Novel Peptide Agonist of Formyl-Peptide Receptor-Like 1 (ALX) Displays Anti-Inflammatory and Cardioprotective Effects (original) (raw)

Title page A novel peptide agonist of FPRL1 (ALX) displays anti-inflammatory and cardioprotective effects Running title page Running title: An anti-inflammatory and cardioprotective agonist of FPRL1

2020

Activation of the Formyl-peptide receptor-like1 (FPRL1) pathway has recently gained high recognition for its significance in therapy of inflammatory diseases. Agonism at FPRL1 affords a beneficial effect in animal models of acute inflammatory conditions, as well as in chronic inflammatory diseases. CGEN-855A is a novel 21 amino acid peptide agonist for FPRL1 and also activates FPRL2. CGEN-855A was discovered using a computational platform designed to predict novel GPCR peptide agonists cleaved from secreted proteins by convertase proteolysis. In vivo, CGEN-855A displays antiinflammatory activity manifested as 50% inhibition of PMN recruitment to inflamed air pouch, and provides protection against ischemia-reperfusion mediated injury to the myocardium in both murine and rat models (36 and 25% reduction in infarct size, respectively). Both these activities are accompanied by inhibition of PMN recruitment to the injured organ. The secretion of inflammatory cytokines, including IL-6, IL-1β, and TNFα, was not affected upon incubation of human peripheral blood mononuclear cells (PBMCs) with CGEN-855A, while IL-8 secretion was elevated up to 2 fold upon treatment with highest CGEN-855A dose only. Collectively, these new data support a potential role for CGEN-855A in the treatment of reperfusion-mediated injury and in other acute and chronic inflammatory conditions.

Are formyl peptide receptors novel targets for therapeutic intervention in ischaemia–reperfusion injury?

Trends in Pharmacological Sciences, 2010

Ischaemia-reperfusion (I/R) injury is a common feature of several diseases associated with high morbidity and mortality, such as stroke and myocardial infarction. The damaged tissue displays cardinal signs of inflammation and microvascular injury that, unless resolved, lead to long-term tissue damage with associated dysfunction. Current therapies are limited and are often associated with many side effects. Increasing evidence suggests that members of the formyl peptide receptor (FPR) family, in particular human FPR2/ALX, might have an important role in the pathophysiology of I/R injury. It was recently demonstrated that several peptides and non-peptidyl small-molecule compounds have antiinflammatory and pro-resolving properties via their action on members of the FPR family. Here I review this evidence and suggest that FPR ligands, particularly in the brain, could be novel and exciting anti-inflammatory therapeutics for the treatment of a variety of clinical conditions, including stroke.

TOLL-LIKE RECEPTORS IN ISCHEMIA-REPERFUSION INJURY

Ischemia-reperfusion (I/R) injuries are implicated in a large array of pathological conditions such as myocardial infarction, cerebral stroke, and hepatic, renal, and intestinal ischemia, as well as following cardiovascular and transplant surgeries. The hallmark of these pathologies is excessive inflammation. Toll-like receptors (TLRs) are recognized as one of the main contributors to pathogen-induced inflammation and, more recently, injury-induced inflammation. Endogenous ligands such as low-molecular hyaluronic acid, fibronectin, heat shock protein 70, and heparin sulfate were all found to be cleaved in the inflamed tissue and to activate TLR2 and TLR4, initiating an inflammatory response even in the absence of pathogens and infiltrating immune cells. In this review, we discuss the contribution of TLR activation in hepatic, renal, cerebral, intestinal, and myocardial I/R injuries. A greater understanding of the role of TLRs in I/R injuries may aid in the development of specific TLR-targeted therapeutics to treat these conditions.

Targeting formyl peptide receptors to facilitate the resolution of inflammation

European Journal of Pharmacology, 2018

The formyl peptide receptors (FPRs) are G protein coupled receptors that recognize a broad range of structurally distinct pathogen and danger-associated molecular patterns and mediate host defense to infection and tissue injury. It became evident that the cellular distribution and biological functions of FPRs extend beyond myeloid cells and governing their activation and trafficking. In recent years, significant progress has been made to position FPRs at check points that control the resolution of inflammation, tissue repair and return to homeostasis. Accumulating data indicate a role for FPRs in an ever-increasing range of human diseases, including atherosclerosis, chronic obstructive pulmonary disease, asthma, autoimmune diseases and cancer, in which dysregulated or defective resolution are increasingly recognized as critical component of the pathogenesis. This review summarizes recent advances on how FPRs 2 recognize distinct ligands and integrate opposing cues to govern various responses and will discuss how this knowledge could be harnessed for developing novel therapeutic strategies to counter inflammation that underlies many human diseases.

RC-3095, a Selective Gastrin-Releasing Peptide Receptor Antagonist, Does Not Protect the Lungs in an Experimental Model of Lung Ischemia-Reperfusion Injury

BioMed Research International, 2015

RC-3095, a selective GRPR antagonist, has been shown to have anti-inflammatory properties in different models of inflammation. However, its protective effect on lungs submitted to lung ischemia-reperfusion injury has not been addressed before. Then, we administrated RC-3095 intravenously before and after lung reperfusion using an animal model of lung ischemia-reperfusion injury (LIRI) by clamping the pulmonary hilum. Twenty Wistar rats were subjected to an experimental model in four groups: SHAM, ischemia-reperfusion (IR), RC-Pre, and RC-Post. The final mean arterial pressure significantly decreased in IR and RC-Pre compared to their values before reperfusion ( < 0.001). The RC-Post group showed significant decrease of partial pressure of arterial oxygen at the end of the observation when compared to baseline ( = 0.005). Caspase-9 activity was significantly higher in the RC-Post as compared to the other groups ( < 0.013). No significant differences were observed in eNOS activity among the groups. The groups RC-Pre and RC-Post did not show any significant decrease in IL-1 ( = 0.159) and TNF-( = 0.260), as compared to IR. The histological score showed no significant differences among the groups. In conclusion, RC-3095 does not demonstrate a protective effect in our LIRI model. Additionally, its use after reperfusion seems to potentiate cell damage, stimulating apoptosis.

Inhibition of FPR2 impaired leukocytes recruitment and elicited non-resolving inflammation in acute heart failure

Pharmacological Research, 2019

Lifestyle or age-related risk factors over-activate the inflammation that triggers acute heart failure (HF)-related mortality following myocardial infarction (MI). Post-MI activated leukocytes express formyl peptide receptor 2 (FPR2) that is essential for inflammation-resolution and in cardiac healing. However, the role of FPR2 in acute HF is incomplete and remain of interest. Here, we aimed to determine whether pharmacological inhibition of FPR2 perturb leukocyte trafficking in acute HF. Male C57BL/6 (8 to 12 weeks) mice were subjected to acute HF (MI-d1) using permanent coronary artery ligation that develops irreversible acute and chronic heart failure. FPR2 antagonist WRW4 (1μg/kg/day) was subcutaneously injected 3 hr post-MI maintaining salineinjected MI-controls. Leukocytes were quantitated using flow cytometry, and acute decompensated HF was confirmed using echocardiography and histology. FPR2 inhibition decreased the expression of FPR2 in the LV and spleen tissues. Administration of WRW4 inhibitor to mice primed immature and inactive neutrophils infiltration Ly6G int and intensified the Ccl2 expression compared to MI-control in the infarcted LV post-MI. Leukocyte profiling revealed an overall decrease in monocytes (23.3±2%) in WRW4-injected mice compared with MI-control (49.1±2%) in infarcted LV. FPR2 inhibition increased F4/80 + /Ly6C hi pro-inflammatory macrophages (14.8±2%) compared with MI-control (10±1%) with increased transcripts of pro-inflammatory markers TNF-α and IL-1β, and decreased Arg-1 expression in the infarcted LV compared to MIcontrols is suggestive of the impaired acute inflammatory response. Inhibition of FPR2 using WRW4 also disturbed splenocardiac leukocytes recruitment by priming immature neutrophils leading to the onset of incomplete resolution signaling in acute decompensated HF post-MI.

Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice

Nature communications, 2017

Effective treatment for managing myocardial infarction (MI) remains an urgent, unmet clinical need. Formyl peptide receptors (FPR) regulate inflammation, a major contributing mechanism to cardiac injury following MI. Here we demonstrate that FPR1/FPR2-biased agonism may represent a novel therapeutic strategy for the treatment of MI. The small-molecule FPR1/FPR2 agonist, Compound 17b (Cmpd17b), exhibits a distinct signalling fingerprint to the conventional FPR1/FPR2 agonist, Compound-43 (Cmpd43). In Chinese hamster ovary (CHO) cells stably transfected with human FPR1 or FPR2, Compd17b is biased away from potentially detrimental FPR1/2-mediated calcium mobilization, but retains the pro-survival signalling, ERK1/2 and Akt phosphorylation, relative to Compd43. The pathological importance of the biased agonism of Cmpd17b is demonstrable as superior cardioprotection in both in vitro (cardiomyocytes and cardiofibroblasts) and MI injury in mice in vivo. These findings reveal new insights fo...

Effects on Leukocyte Responses and Formyl-Peptide Receptor 2 : Ligand-Specific Anti-Inflammatory Role of the Murine

2010

The human formyl-peptide receptor (FPR)-2 is a G protein-coupled receptor that transduces signals from lipoxin A 4 , annexin A1, and serum amyloid A (SAA) to regulate inflammation. In this study, we report the creation of a novel mouse colony in which the murine FprL1 FPR2 homologue, Fpr2, has been deleted and describe its use to explore the biology of this receptor. Deletion of murine fpr2 was verified by Southern blot analysis and PCR, and the functional absence of the G protein-coupled receptor was confirmed by radioligand binding assays. In vitro, Fpr2 2/2 macrophages had a diminished response to formyl-Met-Leu-Phe itself and did not respond to SAA-induced chemotaxis. ERK phosphorylation triggered by SAA was unchanged, but that induced by the annexin A1derived peptide Ac2-26 or other Fpr2 ligands, such as W-peptide and compound 43, was attenuated markedly. In vivo, the antimigratory properties of compound 43, lipoxin A 4 , annexin A1, and dexamethasone were reduced notably in Fpr2 2/2 mice compared with those in wild-type littermates. In contrast, SAA stimulated neutrophil recruitment, but the promigratory effect was lost following Fpr2 deletion. Inflammation was more marked in Fpr2 2/2 mice, with a pronounced increase in cell adherence and emigration in the mesenteric microcirculation after an ischemia-reperfusion insult and an augmented acute response to carrageenan-induced paw edema, compared with that in wild-type controls. Finally, Fpr2 2/2 mice exhibited higher sensitivity to arthrogenic serum and were completely unable to resolve this chronic pathology. We conclude that Fpr2 is an anti-inflammatory receptor that serves varied regulatory functions during the host defense response. These data support the development of Fpr2 agonists as novel anti-inflammatory therapeutics.