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Jimmunol.1900871.Full.Pdf Staphylococcus aureus−Derived PSMα Peptides Activate Neutrophil FPR2 but Lack the Ability to Mediate β-Arrestin Recruitment and Chemotaxis This information is current as of September 25, 2021. Martina Sundqvist, Karin Christenson, Michael Gabl, André Holdfeldt, Karin Jennbacken, Thor C. Møller, Claes Dahlgren and Huamei Forsman J Immunol published online 6 November 2019 http://www.jimmunol.org/content/early/2019/11/05/jimmun Downloaded from ol.1900871 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 6, 2019, doi:10.4049/jimmunol.1900871 The Journal of Immunology Staphylococcus aureus–Derived PSMa Peptides Activate Neutrophil FPR2 but Lack the Ability to Mediate b-Arrestin Recruitment and Chemotaxis Martina Sundqvist,* Karin Christenson,† Michael Gabl,*,1 Andre´ Holdfeldt,* Karin Jennbacken,‡ Thor C. Møller,x Claes Dahlgren,* and Huamei Forsman*,‡ Formyl peptide receptor 2 (FPR2) is a G protein–coupled pattern recognition receptor sensing both mitochondrial- and bacterial- derived formylated peptides, including the PSMa toxins secreted by community-associated methicillin-resistant Staphylococcus aureus strains. Similar to many other FPR2 agonistic peptides, nanomolar concentrations of both PSMa2 and PSMa3 activate neutrophils to increase the cytosolic concentration of Ca2+ and release NADPH oxidase–derived reactive oxygen species. In addition, the PSMa peptides induce FPR2 homologous desensitization, actin polymerization, and neutrophil reactivation through Downloaded from 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 PSMa peptides lacked the ability to recruit b-arrestin and induce neutrophil chemotaxis, supporting the previous notion that b-arrestin translocation is of importance for cell migration. Despite the lack of b-arrestin recruitment, the PSMa peptides induced an FPR2-dependent ERK1/2 phosphorylation and internalization. Furthermore, structure-activity relationship analysis with PSMa2 derivatives revealed critical roles of the first 3 aa linked to N-fMet as well as the C terminus of PSMa2 in promoting FPR2 to recruit b-arrestin. In summary, our data demonstrate a novel neutrophil http://www.jimmunol.org/ activation pattern upon FPR2 sensing of PSMa peptides, signified by the ability to induce increased intracellular Ca2+, ERK1/2 phosphorylation, internalization, and NADPH oxidase activity, yet lack of b-arrestin recruitment and neutrophil chemoattraction. These novel features adopted by the PSMa peptides could be of importance for S. aureus virulence and might facilitate identi- fication of new therapeutic strategies for treating S. aureus infections. The Journal of Immunology, 2019, 203: 000–000. taphylococcus aureus are both commensals that colonize give rise to lethal systemic infections (1, 2). Highly pathogenic about one-third of all humans, and pathogens that cause a community-associated methicillin-resistant S. aureus (MRSA) variety of infections in different organs where they may strains have, in addition to the resistance to multiple antibi- S by guest on September 25, 2021 otics, acquired additional virulence factors that enable them to cause more aggressive infections (2, 3). Host interaction with *Department of Rheumatology and Inflammation Research, University of Gothen- S. aureus is complex, because the bacteria not only release a burg, Gothenburg, 413 46 Sweden; †Department of Oral Microbiology and Immu- large number of virulence factors, including peptides that in- nology, Institute of Odontology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, 405 30 Sweden; ‡Bioscience Cardiovascular, Research and Early De- hibit the function of neutrophil chemoattractant receptors (4), velopment, Cardiovascular, Renal and Metabolism, Biopharmaceuticals Research but also secrete neutrophil-activating peptides, including the for- x and Development, AstraZeneca, Gothenburg, 431 83 Sweden; and Department of mylated tetrapeptide fMIFL, a potent/high-affinity agonist for one Drug Design and Pharmacology, University of Copenhagen, Copenhagen, 2100 Denmark of the chemoattractant receptors termed formyl peptide receptor 1Current address: Sahlgrenska Cancer Center, Department of Infectious Diseases, (FPR) 1 (5). In addition, community-associated MRSA strains Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. release genomic DNA–encoded formylated phenol-soluble mod- ORCIDs: 0000-0003-1254-5158 (K.J.); 0000-0002-2256-577X (T.C.M.). ulin a (PSMa) peptides, which at low nanomolar concentrations Received for publication July 23, 2019. Accepted for publication October 4, 2019. activate FPR2 (another chemoattractant receptor in the FPR This work was supported by the Swedish Research Council (005601 and 02448 to family) and at high nanomolar concentrations permeabilize host H.F and C.D.), the Swedish Foundation for Strategic Research (SM17-0046 to H.F.), cell membranes and induce cytotoxicity (6–9). Thus, the FPRs are the King Gustaf V 80-Year Foundation (FAI 2014-0011 to C.D.), the Swedish gov- critical players in S. aureus infections, but their precise roles/ ernment under the ALF agreement (ALFGBG 72510 to C.D.), the Ake˚ Wibergs Foundation (M15-005 to H.F.), the Magnus Bergwalls Foundation (2018-02579 functions are not entirely understood. to M.S.), the Ingabritt and Arne Lundberg Foundation and the European Union’s Neutrophil-expressed FPR1 and FPR2 belong to the large family of Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie Grant G protein–coupled receptors (GPCRs) and display high affinity for Agreement No. 797497 to T.C.M). formylated peptides of both bacterial and host mitochondrial origin M.S., H.F., and C.D. designed the study and wrote the manuscript. M.S., K.C., M.G., A.H., and T.C.M. performed the experiments with input from H.F., C.D., and K.J. (10, 11). To date, all characterized mitochondrial-derived formyl M.S., H.F., K.C., and T.C.M. analyzed the data. All authors edited and proofread peptides trigger, despite differences in FPR preference, similar sig- the final version of the manuscript. naling and functional responses that include a G protein–dependent Address correspondence and reprint requests to Dr. Huamei Forsman, Department of rise in the cytosolic concentration of free calcium ([Ca2+] ) through Rheumatology and Inflammation Research, University of Gothenburg, Guldhedsgatan i 10 A, S-413 46 Gothenburg, Sweden. E-mail address: [email protected] the PLC-PIP2-IP3 pathway and the release of reactive oxygen species Abbreviations used in this article: AF647, Alexa Fluor 647; FPR, formyl peptide (ROS) generated by the phagocyte NADPH oxidase (12). In addition receptor; GPCR, G protein–coupled receptor; LA, Latrunculin A; MRSA, to formyl peptides, both FPR1 and FPR2 recognize also a number methicillin-resistant S. aureus; MSD, Meso Scale Discovery; PAF, platelet- of endogenous and exogenous inflammatory mediators as well as activating factor; PSMa, phenol-soluble modulin a; ROS, reactive oxygen species. synthetic compounds that lack the formylated methionine hallmark Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 (13, 14). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900871 2 FUNCTIONAL SELECTIVITY OF PSMa PEPTIDES The precise signaling pathways downstream of FPRs have Sweden. According to the Swedish legislation section code 4x 3p SFS not yet been elucidated in detail, but it is generally accepted 2003:460 (Lag om etikpro¨vning av forskning som avser ma¨nniskor), no that the receptors mediate inflammatory responses through ethical approval was needed, as all blood samples were provided anony- mously and thereby could not be traced back to a specific donor. Gai-dependent signaling pathways upon activation (15). In line with the emerging concept of biased signaling/functional Isolation of human neutrophils selectivity for other GPCRs, FPR2 ligand–directed biased Neutrophils were isolated from buffy coats or from peripheral blood ob- signaling and selective responses (pro- and anti-inflammatory) tained from healthy volunteers as described (23, 24). Briefly, after dextran have been reported (16–18). Receptor-recruited b-arrestin is a sedimentation at room temperature, remaining erythrocytes were disrupted critical determinant for receptor desensitization and initiation by hypotonic lysis, and neutrophils were obtained following a Ficoll-Paque gradient centrifugation. The purified cells were washed, resuspended in KRG of G protein–independent ERK1/2 signaling downstream of 7 (1 3 10 /ml), and stored on ice until use. many activated GPCRs
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