title: Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections.
abstract: Production of antimicrobial peptides by epithelia is an essential defense against infectious pathogens. In this study we evaluated whether the commensal microorganism Staphylococcus epidermidis may enhance production of antimicrobial peptides by keratinocytes and thus augment skin defense against infection. Exposure of cultured undifferentiated human keratinocytes to a sterile nontoxic small molecule of <10 kDa from S. epidermidis conditioned culture medium (SECM), but not similar preparations from other bacteria, enhanced human beta-defensin 2 (hBD2) and hBD3 mRNA expression and increased the capacity of cell lysates to inhibit the growth of group A Streptococcus (GAS) and S. aureus. Partial gene silencing of hBD3 inhibited this antimicrobial action. This effect was relevant in vivo as administration of SECM to mice decreased susceptibility to infection by GAS. Toll-like receptor 2 (TLR2) was important to this process as a TLR2-neutralizing antibody blocked induction of hBDs 2 and 3, and Tlr2-deficient mice did not show induction of mBD4. Taken together, these findings reveal a potential use for normal commensal bacterium S. epidermidis to activate TLR2 signaling and induce antimicrobial peptide expression, thus enabling the skin to mount an enhanced response to pathogens.
authors.affiliation: Division of Dermatology, Department of Medicine, University of California, San Diego and VA San Diego Healthcare System, San Diego, California 92161, USA.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Lai
authors.forename: Anna L
authors.initials: AL
authors.lastname: Cogen
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Radek
authors.forename: Hyun Jeong
authors.initials: HJ
authors.lastname: Park
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Macleod
authors.forename: Anke
authors.initials: A
authors.lastname: Leichtle
authors.forename: Allen F
authors.initials: AF
authors.lastname: Ryan
authors.forename: Anna
authors.initials: A
authors.lastname: Di Nardo
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D001426:Bacterial Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology / Q000382:microbiology; D020868:Gene Silencing; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D013207:Staphylococcal Skin Infections / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D013211:Staphylococcus aureus; D013212:Staphylococcus epidermidis; D013290:Streptococcal Infections / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D013297:Streptococcus pyogenes; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*; D023083:beta-Defensins / Q000235:genetics / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D001426:Bacterial Proteins; D017077:Culture Media, Conditioned; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D023083:beta-Defensins
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