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Review
. 2015 May;185(5):1172-84.
doi: 10.1016/j.ajpath.2015.01.020. Epub 2015 Mar 17.

The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation

David A Dorward  1 , Christopher D Lucas  2 , Gavin B Chapman  2 , Christopher Haslett  2 , Kevin Dhaliwal  2 , Adriano G Rossi  2
Affiliations
Review

The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation

David A Dorward et al. Am J Pathol. 2015 May.

Abstract

Neutrophil migration to sites of inflammation and the subsequent execution of multiple functions are designed to contain and kill invading pathogens. These highly regulated and orchestrated processes are controlled by interactions between numerous receptors and their cognate ligands. Unraveling and identifying those that are central to inflammatory processes may represent novel therapeutic targets for the treatment of neutrophil-dominant inflammatory disorders in which dysregulated neutrophil recruitment, function, and elimination serve to potentiate rather than resolve an initial inflammatory insult. The first G protein-coupled receptor to be described on human neutrophils, formyl peptide receptor 1 (FPR1), is one such receptor that plays a significant role in the execution of these functions through multiple intracellular signaling pathways. Recent work has highlighted important observations with regard to both receptor function and the importance and functional relevance of FPR1 in the pathogenesis of a range of both sterile and infective inflammatory conditions. In this review, we explore the multiple components of neutrophil migration and function in both health and disease, with a focus on the role of FPR1 in these processes. The current understanding of FPR1 structure, function, and signaling is examined, alongside discussion of the potential importance of FPR1 in inflammatory diseases suggesting that FPR1 is a key regulator of the inflammatory environment.

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Figures

Figure 1
Figure 1
Structure of the FPR1 receptor and key polymorphisms within the protein. Formyl peptide receptor 1 (FPR1) as a classic G-protein–coupled receptor has seven transmembrane-spanning regions with an extracellular N-terminus, whereas the C-terminus is found within the cytoplasm. Multiple amino acid substitutions have been found within the protein: recognized constitutive isoforms (green; FPR-26, FPR-98, and FPR-G6), polymorphisms associated with disease states including juvenile and aggressive periodontitis (red), hypertension in young adults (orange), gastric cancer (pink; denotes D192K), and those that have been observed but whose functional significance remains uncertain (blue).
Figure 2
Figure 2
Intracellular signaling events after FPR1 receptor activation. After binding of ligand to formyl peptide receptor 1 (FPR1), conversion of guanosine diphosphate to guanosine triphosphate induces dissociation of the α from the βγ subunits. These trigger a range of intracellular kinase pathways, resulting in the induction of a variety of cell functions, including neutrophil chemotaxis, degranulation, superoxide anion production, and transcriptional activity. The predominant signaling pathways are those of phosphoinositide-3 kinase (PI3K), mitogen-activated protein kinase (MAPK), and phospholipase C. The latter triggers release of intracellular calcium from the endoplasmic reticulum to activate protein kinase C (PKC) and subsequent reactive oxygen species production, whereas PI3K triggers protein kinase B (alias Akt)-mediated and phosphoinositol-3,4,5-trisphosphate (PIP3)-mediated signaling, with a variety of cellular effects. With PI3K pulled toward the plasma membrane by the β and γ G-protein subunits (Gβ and Gγ), activation of Ras family proteins and MAPK further contributes to oxidative burst and chemotaxis. CDC, cell division control protein; DAG, diacyl glycerol; Gα, G-protein α; GEF, guanine nucleotide exchange factor; Grb, growth factor receptor–bound protein; IP3, inositol trisphosphate; MEKK, mitogen-activated protein kinase kinase; PA, phosphatidic acid; PLCβ, phospholipase Cβ; PLD, phospholipase D; RAF, rapidly accelerated fibrosarcoma; Sos, son of sevenless; WASP, Wiskott-Aldrich syndrome protein.
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