Formyl-Peptide Receptors in Infection, Inflammation, and Cancer

Formyl-peptide receptors (FPRs) belong to the family of seven-transmembrane G protein-coupled receptors, which are involved in host defense against infections and in clearance of damaged host cells. FPR1 is activated by short N-formylated peptides; these are cleavage products of bacterial and mitochondrial proteins. FPR2 is activated by endogenous non-formylated ligands as well as by longer amphipathic, α-helical bacterial peptides such as staphylococcal phenol-soluble modulins. Endogenous FPR2 ligands can increase host survival during bacterial infections by reducing bacterial loads and by preventing excessive inflammatory responses. FPRs are critical for effective healing of sterile wounds, as they can mediate the first wave of neutrophil infiltration. FPR expression is associated with tumor progression in various cancer types. However, chemotherapy-induced tumor regression can also require FPR1 expression. Formyl-peptide receptors (FPRs) recognize bacterial and mitochondrial formylated peptides as well as endogenous non-formylated peptides and even lipids. FPRs are expressed on various host cell types but most strongly on neutrophils and macrophages. After the discovery of FPRs on leukocytes, it was assumed that these receptors predominantly govern a proinflammatory response resulting in chemotaxis, degranulation, and oxidative burst during infection. However, it is clear that the activation of FPRs has more complex consequences and can also promote the resolution of inflammation. Recent studies have highlighted associations between FPR function and inflammatory conditions, including inflammatory disorders, cancer, and infection. In this review we discuss these recent findings. Formyl-peptide receptors (FPRs) recognize bacterial and mitochondrial formylated peptides as well as endogenous non-formylated peptides and even lipids. FPRs are expressed on various host cell types but most strongly on neutrophils and macrophages. After the discovery of FPRs on leukocytes, it was assumed that these receptors predominantly govern a proinflammatory response resulting in chemotaxis, degranulation, and oxidative burst during infection. However, it is clear that the activation of FPRs has more complex consequences and can also promote the resolution of inflammation. Recent studies have highlighted associations between FPR function and inflammatory conditions, including inflammatory disorders, cancer, and infection. In this review we discuss these recent findings. secreted during the acute phase of inflammation predominantly by the liver. belongs to the annexin family of Ca2+-dependent phospholipid-binding proteins. It suppresses phospholipase A2 and inhibits various leukocyte inflammatory events. homologous desensitization leaves a cell transiently unresponsive to agents that activate the desensitized receptor, whereas heterologous desensitization leaves a cell transiently unresponsive to agents that activate related receptors. subdomains in the plasma membrane that contain high concentrations of cholesterol and glycosphingolipids. They exist as distinct liquid-ordered regions of the membrane that are resistant to extraction with non-ionic detergents. represents a bioactive metabolite of arachidonic acid made by various cell types (e.g., neutrophils). LXA4 is formed during inflammatory responses and contributes to resolving inflammatory responses. enzyme which cleaves various synthetic substrates with Arg or Lys at the P1 position and prefers small side-chain amino acids, such as Ala and Gly, at the P2 position. molecules with conserved patterns derived from pathogens (e.g., lipopolysaccharide) which are recognized by cells of the innate immune system. They are recognized by PRRs in both plants and animals. germline-encoded host receptors. They are expressed by cells of the innate immune system, such as macrophages and neutrophils, but also by other cell types (e.g., epithelial cells). PRRs identify pathogen-associated molecular patterns, which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host cells that are released during cell damage. family of protein toxins produced by staphylococci. They are encoded within the core genome and constitute important virulence factors. They activate leukocytes via FPR2. endogenous chemical mediator that exerts potent anti-inflammatory and proresolving activities by acting on GPCRs. defined as systemic SIRS in response to an infectious process, whereas sepsis-like syndrome describes SIRS without infection. form of inflammation (in the absence of infection) caused by mechanical trauma, ischemia, stress, or environmental conditions. These conditions induce the secretion of molecular agents collectively termed DAMPs. describes the presence of at least two of the following symptoms: abnormal body temperature, heart rate, respiratory rate, and increased white blood cell count. play a key role in the innate immune system. These receptors are usually expressed in macrophages as well as dendritic cells and recognize structurally conserved molecules derived from microbes (e.g., lipopolysaccharides or lipopeptides).