The Role of Formylated Peptides and Formyl Peptide Receptor 1 in Governing Neutrophil Function during Acute Inflammation

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.

Impaired intracellular signaling, myeloperoxidase release and bactericidal activity of neutrophils from patients with alcoholic cirrhosis

“…MPO biological importance is further illustrated in the findings in MPO-knockout mice of increased infections by Klebsiella and Candida, increased mortality [4] and prolonged inflammation [5]. MPO release and ROS production are triggered by various pro-inflammatory mediators among which bacterial formylated peptides which also act as chemoattractants, thus alerting neutrophils in case of infection through stimulation of fPR, a G-protein coupled receptor [11]. Neutrophil antibacterial activities are tightly regulated by signaling events triggered via fPR including phospholipases, G-proteins, protein kinases such as protein kinase C (PKC), mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin [6][7][8].…”

“…Neutrophil antibacterial activities are tightly regulated by signaling events triggered via fPR including phospholipases, G-proteins, protein kinases such as protein kinase C (PKC), mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin [6][7][8]. Signaling impairment under pathological situations or by drugs leads to neutrophil dysfunctions, which are detrimental to host-defense [9][10][11].…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…With the emergence of molecular imaging, new sensitive and selective imaging probes have been developed that can be translated from animal models to patients. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging can detect and monitor a variety of pathophysiological processes such as T cell activity by glucose uptake and neutrophil activation by binding of the peptide cinnamoyl-F-(D)L-F-(D)L-F (cFLFLF) to the formyl peptide receptor 1 (FPR1) (48)(49)(50). Multiphoton intravital microscopy can also be used to assess specific cell populations and functions during murine IRI (51)(52)(53).…”

Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury

“…Many downstream signaling pathways are transduced by FPR1, including cAMP/PKA, calcium mobilization, MAPK, and Akt signaling [11]. The PKA inhibitor H89 is unable to abolish the inhibitory effects of GMC on fMLF-induced superoxide anion production and elastase release.…”

“…These receptors are responsible for sensing various endogenous and exogenous molecular stimuli to mediate neutrophil activation during inflammation [8,9]. N-formyl peptides derived from invading microorganisms or endogenous host mitochondria strongly bind to FPR1 to trigger septic or sterile inflammatory responses [10,11]. The binding of N-formyl peptides to FPR1 activates neutrophils and guides their migration into infected or injured tissues.…”