Studies on Human Neutrophil Biological Functions by Means of Formylpeptide Receptor Agonists and Antagonists

Abstract

Phagocytes are activated by several extracellular signals, including formyl-peptides derived from bacterial proteins or disrupted cells. The most intensely studied member of the formylpeptide family is the synthetic tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), whose specific receptors have been identified on neutrophil plasma membrane and subsequently cloned. The fMLP-receptor interaction activates multiple transduction pathways responsible for various neutrophil functions such as adhesion, chemotaxis, exocytosis of secretory granules and superoxide anion production, which represent the physiological response to bacterial infection and tissue damage. An unresolved question is whether signaling requirements are identical or specific for each physiological function. The development of fMLP receptor agonists and antagonists has led to an improvement of our knowledge about the above issue. Of particular interest is the possibility that receptorial antagonists, able to transiently inhibit neutrophil responses to formylpeptides, could be therapeutic agents in the treatment of inflammation-related diseases. Aim of this review is, i) to summarise the current understanding of the series of events that begins at the level of formylpeptide-receptor interaction and is responsible for the activation of transduction pathways, which finally determine neutrophil response; ii) to define the state of art regarding the synthesis as well as the biological actions of fMLP receptor agonists and antagonists.

Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes

“…The FPR mediates migration toward fMLP, a strong bacterial chemotactic agent. 49 Aquaporin-9 regulates water influx, which is necessary for lamellipodium formation during migration. Aquaporin-9 selectively associates with FPR in migrating granulocytes.…”

Differential Contribution of BacterialN-Formyl-Methionyl-Leucyl- Phenylalanine and Host-Derived CXC Chemokines to Neutrophil Infiltration into Pulmonary Alveoli during Murine Pneumococcal Pneumonia

“…The role of N-formyl peptides as chemoattractant molecules has been studied widely (10,14,15,29). However, the influence of fMLP on the orchestration of leukocyte responses in bacterial infections remains poorly investigated.…”

“…Pathogen-derived factors such as Nformyl peptides have also been shown to exert strong PMN chemotaxis in vitro and in animal models (9,14). These soluble peptides are small by-products of protein synthesis released by bacteria into their environment (16).…”

Oxidation of methionine 63 and 83 regulates the effect of S100A9 on the migration of neutrophils in vitro

“…fMLP, a bacterial tripeptide, exerts powerful chemoattractant effects on neutrophils, including chemotaxis and chemokinesis [28]. S100A9 mutants, in which alanine replaced Met63 and Met83, significantly inhibited the chemotaxis effect of fMLP (Fig.…”