title: Vigilant keratinocytes trigger pathogen-associated molecular pattern signaling in response to streptococcal M1 protein.
abstract: The human skin exerts many functions in order to maintain its barrier integrity and protect the host from invading microorganisms. One such pathogen is Streptococcus pyogenes, which can cause a variety of superficial skin wounds that may eventually progress into invasive deep soft tissue infections. Here we show that keratinocytes recognize soluble M1 protein, a streptococcal virulence factor, as a pathogen-associated molecular pattern to release alarming inflammatory responses. We found that this interaction initiates an inflammatory intracellular signaling cascade involving the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal protein kinase and the subsequent induction and mobilization of the transcription factors NF-κB and AP-1. We also determined the imprint of the inflammatory mediators released, such as interleukin-8 (IL-8), growth-related oncogene alpha, migration inhibitory factor, extracellular matrix metalloproteinase inducer, IL-1α, IL-1 receptor a, and ST2, in response to streptococcal M1 protein. The expression of IL-8 is dependent on Toll-like receptor 2 activity and subsequent activation of the mitogen-activated protein kinases ERK and p38. Notably, this signaling seems to be distinct for IL-8 release, and it is not shared with the other inflammatory mediators. We conclude that keratinocytes participate in a proinflammatory manner in streptococcal pattern recognition and that expression of the chemoattractant IL-8 by keratinocytes constitutes an important protective mechanism against streptococcal M1 protein.
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Biomedical Center (BMC), Lund University, Lund, Sweden sandra.persson@med.lu.se.
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Persson
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Biomedical Center (BMC), Lund University, Lund, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Wilk
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Biomedical Center (BMC), Lund University, Lund, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences, Biomedical Center (BMC), Lund University, Lund, Sweden.
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
mesh_terms: D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051926:Basigin / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002461:Cell Line, Transformed; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D015603:Keratinocytes / Q000276:immunology* / Q000382:microbiology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D054360:Chemokine CXCL1; C079241:IL1RL1 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D000072179:Interleukin-1 Receptor-Like 1 Protein; D053582:Interleukin-1alpha; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; C580778:MAPKBP1 protein, human; D008263:Macrophage Migration-Inhibitory Factors; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D018808:Transcription Factor AP-1; C014689:streptococcal M protein; D051926:Basigin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human