Recognition by leukocyte formyl peptide receptors. Promiscuous binding or pattern recognition?

Abstract

Neutrophil granulocytes play an important role in the early stages of microbial infection. The neutrophils have to leave the blood stream and migrate out into the tissue where they phagocytose microbes and cell debris from damaged host tissues. Their antimicrobial substances might also contribute to the tissue injury commonly associated with inflammation. Migration to the inflammatory site is directed by chemoattractants, which guide and activate neutrophils via specific receptors. One important class of receptors is the group of formyl peptide receptors (FPRs) of which two members are expressed on human neutrophils, FPR and FPR-like 1 (FPRL1). These receptors display large sequence homologies and belong to a larger family of G-protein-coupled receptors. FPR recognizes formylated peptides generated during bacterial growth and can thus be viewed as a "pattern recognition receptor", while FPRL1 was until recently an orphan receptor with unknown functions and agonists.A cecropin-like antibacterial peptide from the gastric pathogen Helicobacter pylori, Hp(2-20), was found to be a complete neutrophil activator that mediates chemotaxis, induces granule mobilization and activates the NADPH-oxidase to release oxygen free radicals. The receptor utilized by Hp(2-20) was identified as FPRL1. This receptor has in the last years been shown to recognize a large number of peptides/proteins, many of which represent cleavage products of full-length proteins in themselves unable to activate the receptor. Thus, also FPRL1 could be considered a "pattern recognition receptor" activated indirectly by the proteolytic cascades accompanying tissue damage. The Hp(2-20)-induced activity was increased when neutrophil storage-organelles were mobilized to the plasma membrane by incubation with bacterial lipopolysaccharide (LPS). A large pool of FPRL1 was found in the easily mobilized gelatinase granules, implying that the enhanced response was due to receptor upregulation by granule mobilization. Also murine neutrophils responded to FPR/FPRL1 agonists, an activation partly subjected to the same regulatory events as human neutrophils. However, important differences between cells from the two species were also found. Neutrophils from mice and men differ not only in relative abundance, but also in receptor arsenals, suggesting that humans and mice have developed distinct sensitivities towards different agonists due to co-evolution with different pathogens.