Ligand recognition and activation of formyl peptide receptors in neutrophils

Abstract

Neutrophil granulocytes, professional phagocytes of the innate immune system, can migrate in response to gradients of chemoattractants, soluble molecules serving as “danger signals.” The chemotactic behavior of these cells is of great importance for the outcome of the continuously ongoing combat with invading microorganisms. In a number of inflammatory disorders, the chemoattractant-guided accumulation of neutrophils and their subsequent release of reactive oxygen species (ROS) and proteolytic enzymes are responsible for the tissue damage associated with such disease conditions. Research about the structure and function of neutrophil chemoattractants and their receptors is therefore of direct clinical importance and relevance. Although chemotaxis was defined already as an important part of active immune reactivity already by Elie Metchnikoff in the late 19th century [1], the modern chemotaxis research era started first, by the introduction of a filter technique in 1962 [2], which allowed quantitative determinations of neutrophil migration and a rational search for specific attractants derived from intruding microbes or activated/damaged host cells [3]. Following the discovery of bacteria-derived, formylated peptides as potent neutrophil chemoattractants in the mid-1970s [4], the list of structurally well-characterized leukocyte chemoattractants has steadily grown. Other microbial components, cleavage products from the complement system (e.g., C5a), lipid metabolites such as platelet-activating factor (PAF) and leukotriene B4 (LTB4), as well as a large group of chemokines are examples of such molecules [5] (Table 1). During the last two decades, a broad application of molecular biology techniques has also led to identification of the chemoattractant receptors. Despite the fact that these receptors recognize different chemoattractants specifically, they exhibit some sequence homologies and share structural features, all belonging to a pertussis toxin (PTX)-sensitive subfamily within the G protein-coupled receptor (GPCR) superfamily. The reader is referred to several excellent review articles, which in more detail, discuss general aspects of the chemoattractant receptor family and neutrophil activation in inflammation [5 –7, 16]. We intend to summarize the current knowledge about structure and function of two closely related neutrophil G proteincoupled chemoattractant receptors: the FPR, which was the first characterized member in the FPR family, and the closely related FPRL1, also called LXA4 receptor, as this eicosanoid was the first specific agonist described for the receptor. A large number of agonists for these receptors have now been identified, and the same basic neutrophil functional responses are triggered by ligation of these receptors [16]—chemotaxis, receptor mobilization, secretion of proteolytic enzymes and inflammatory mediators, and production of ROS. Ligand recognition by the two neutrophil FPR, linked to activation and signaling, is the subject of this review.