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Regulation of Inflammation and Oxidative Stress by Formyl Peptide Receptors in Cardiovascular Disease Progression.

ABSTRACT: G protein-coupled receptors (GPCRs) are the most important regulators of cardiac function and are commonly targeted for medical therapeutics. Formyl-Peptide Receptors (FPRs) are members of the GPCR superfamily and play an emerging role in cardiovascular pathologies. FPRs can modulate oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production whose dysregulation has been observed in different cardiovascular diseases. Therefore, many studies are focused on identifying molecular mechanisms of the regulation of ROS production. FPR1, FPR2 and FPR3 belong to the FPRs family and their stimulation triggers phosphorylation of intracellular signaling molecules and nonsignaling proteins that are required for NADPH oxidase activation. Some FPR agonists trigger inflammatory processes, while other ligands activate proresolving or anti-inflammatory pathways, depending on the nature of the ligands. In general, bacterial and mitochondrial formylated peptides activate a proinflammatory cell response through FPR1, while Annexin A1 and Lipoxin A4 are anti-inflammatory FPR2 ligands. FPR2 can also trigger a proinflammatory pathway and the switch between FPR2-mediated pro- and anti-inflammatory cell responses depends on conformational changes of the receptor upon ligand binding. Here we describe the detrimental or beneficial effects of the main FPR agonists and their potential role as new therapeutic and diagnostic targets in the progression of cardiovascular diseases.

SUBMITTER: Caso VM

PROVIDER: S-EPMC7998928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Inflammation is associated with a variety of diseases. The hallmark of inflammation is leukocyte infiltration at disease sites in response to pathogen- or damage-associated chemotactic molecular patterns (PAMPs and MAMPs), which are recognized by a superfamily of seven transmembrane, Gi-protein-coupled receptors (GPCRs) on cell surface. Chemotactic GPCRs are composed of two major subfamilies: the classical GPCRs and chemokine GPCRs. Formyl-peptide receptors (FPRs) belong to the classical chemotactic GPCR subfamily with unique properties that are increasingly appreciated for their expression on diverse host cell types and the capacity to interact with a plethora of chemotactic PAMPs and MAMPs. Three FPRs have been identified in human: FPR1-FPR3, with putative corresponding mouse counterparts. FPR expression was initially described in myeloid cells but subsequently in many non-hematopoietic cells including cancer cells. Accumulating evidence demonstrates that FPRs possess multiple functions in addition to controlling inflammation, and participate in the processes of many pathophysiologic conditions. They are not only critical mediators of myeloid cell trafficking, but are also implicated in tissue repair, angiogenesis and protection against inflammation-associated tumorigenesis. A series recent discoveries have greatly expanded the scope of FPRs in host defense which uncovered the essential participation of FPRs in step-wise trafficking of myeloid cells including neutrophils and dendritic cells (DCs) in host responses to bacterial infection, tissue injury and wound healing. Also of great interest is the FPRs are exploited by malignant cancer cells for their growth, invasion and metastasis. In this article, we review the current understanding of FPRs concerning their expression in a vast array of cell types, their involvement in guiding leukocyte trafficking in pathophysiological conditions, and their capacity to promote the differentiation of immune cells, their participation in tumor-associated inflammation and cancer progression. The close association of FPRs with human diseases and cancer indicates their potential as targets for the development of therapeutics.

Project description:The N-formyl peptide receptors (FPRs) are a family of G-protein coupled receptors that respond to proinflammatory N-formylated bacterial peptides (e.g., formyl-Met-Leu-Phe, fMLF) and, thus, contribute to the host response to bacterial infection. Paradoxically, a growing body of evidence suggests that some members of this receptor family may also be targets for certain anti-inflammatory molecules, including annexin A1 (ANXA1), which is an important mediator of glucocorticoid (GC) action. To explore further the potential role of FPRs in mediating ANXA1 actions, we have focused on the pituitary gland, where ANXA1 has a well-defined role as a cell-cell mediator of the inhibitory effects of GCs on the secretion of corticotrophin (ACTH), and used molecular, genetic, and pharmacological approaches to address the question in well-established rodent models. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis identified mRNAs for four FPR family members in the mouse anterior pituitary gland, Fpr-rs1, Fpr-rs2, Fpr-rs6, and Fpr-rs7. Functional studies confirmed that, like dexamethasone, ANXA1 and two ANXA1-derived peptides (ANXA1(1-188) and ANXA1(Ac2-26)) inhibit the evoked release of ACTH from rodent anterior pituitary tissue in vitro. Fpr1 gene deletion failed to modify the pituitary responses to dexamethasone or ANXA1(Ac2-26). However, lipoxin A4 (LXA4, 0.02-2 microM, a lipid mediator with high affinity for Fpr-rs1) mimicked the inhibitory effects of ANXA1 on ACTH release as also did fMLF in high (1-100 microM) but not lower (10-100 nM) concentrations. Additionally, a nonselective FPR antagonist (Boc1, 100 microM) overcame the effects of dexamethasone, ANXA1(1-188), ANXA1(Ac2-26), fMLF, and LXA4 on ACTH release, although at a lower concentration (50 microM), it was without effect. Together, the results suggest that the actions of ANXA1 in the pituitary gland are independent of Fpr1 but may involve other FPR family members, in particular, Fpr-rs1 or a closely related receptor. They thus provide the first evidence for a role of the FPR family in the regulation of neuroendocrine function.

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Regulation of Inflammation and Oxidative Stress by Formyl Peptide Receptors in Cardiovascular Disease Progression.

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