Staphylococcus aureus -Derived PSMα Peptides Activate Neutrophil FPR2 but Lack the Ability to Mediate β-Arrestin Recruitment and Chemotaxis

• Published in: The Journal of immunology (1950) 2019-12, Vol.203 (12), p.3349-3360
• Main Authors: Sundqvist, Martina, Christenson, Karin, Gabl, Michael, Holdfeldt, André, Jennbacken, Karin, Møller, Thor C, Dahlgren, Claes, Forsman, Huamei
• Format: Article
• Language: English
• Subjects: beta-Arrestins - metabolism; Biomarkers; Cell and Molecular Biology; Cell- och molekylärbiologi; Chemotaxis, Leukocyte - immunology; Host-Pathogen Interactions; Humans; Immunohistochemistry; Immunologi inom det medicinska området; Immunology in the medical area; Microbiology in the medical area; Mikrobiologi inom det medicinska området; NADPH Oxidases - metabolism; Neutrophil Activation - immunology; Neutrophils - immunology; Neutrophils - metabolism; Reactive Oxygen Species - metabolism; Receptors, Formyl Peptide - metabolism; Receptors, Lipoxin - metabolism; Staphylococcal Infections - immunology; Staphylococcal Infections - metabolism; Staphylococcal Infections - microbiology; Staphylococcus aureus - immunology
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1900871

Formyl peptide receptor 2 (FPR2) is a G protein-coupled pattern recognition receptor sensing both mitochondrial- and bacterial-derived formylated peptides, including the PSMα toxins secreted by community-associated methicillin-resistant strains. Similar to many other FPR2 agonistic peptides, nanomolar concentrations of both PSMα2 and PSMα3 activate neutrophils to increase the cytosolic concentration of Ca and release NADPH oxidase-derived reactive oxygen species. In addition, the PSMα peptides induce FPR2 homologous desensitization, actin polymerization, and neutrophil reactivation through a receptor cross-talk mechanism. However, in contrast to conventional FPR2 agonistic peptides, including the host-derived formyl peptide MCT-ND4, we found that the PSMα peptides lacked the ability to recruit β-arrestin and induce neutrophil chemotaxis, supporting the previous notion that β-arrestin translocation is of importance for cell migration. Despite the lack of β-arrestin recruitment, the PSMα peptides induced an FPR2-dependent ERK1/2 phosphorylation and internalization. Furthermore, structure-activity relationship analysis with PSMα2 derivatives revealed critical roles of the first 3 aa linked to N-fMet as well as the C terminus of PSMα2 in promoting FPR2 to recruit β-arrestin. In summary, our data demonstrate a novel neutrophil activation pattern upon FPR2 sensing of PSMα peptides, signified by the ability to induce increased intracellular Ca , ERK1/2 phosphorylation, internalization, and NADPH oxidase activity, yet lack of β-arrestin recruitment and neutrophil chemoattraction. These novel features adopted by the PSMα peptides could be of importance for virulence and might facilitate identification of new therapeutic strategies for treating infections.