title: Genetic Variation in TLR10, an Inhibitory Toll-Like Receptor, Influences Susceptibility to Complicated Skin and Skin Structure Infections.
abstract: BACKGROUND
  Toll-like receptors (TLRs) play a central role in the innate immune response to complicated skin and skin structure infections (cSSSIs), with TLR10 being the first family member known to have an inhibitory function. This study assessed the role of TLR10 in recognition of cSSSI-related pathogens and whether genetic variation in TLR10 influences susceptibility to cSSSIs.
  
  
  METHODS
  Human peripheral blood mononuclear cells (PBMCs) preincubated with anti-TLR10 antibody and HEK-293 cells overexpressing TLRs were exposed to cSSSI pathogens, and cytokine secretion was determined by enzyme-linked immunosorbent assay. A total of 318 patients with cSSSI and 328 healthy controls were genotyped for 4 nonsynonymous single-nucleotide polymorphisms in TLR10, and functional consequences of the TLR10 SNPs were assessed via in vitro stimulation assays.
  
  
  RESULTS
  PBMC stimulation with cSSSI pathogens in the presence of TLR10 neutralizing antibody significantly increased interleukin 6 secretion. Overexpression of TLR10 completely abrogated TLR2-induced interleukin 8 secretion by HEK-293 cells in response to cSSSI pathogens. Three polymorphisms in TLR10, I775L, I369L, and N241H, were associated with reduced susceptibility to cSSSIs. The presence of the TLR10 alleles 775L, 369L, or 241H increased interleukin 6 secretion by PBMCs in response to cSSSI pathogens.
  
  
  CONCLUSIONS
  TLR10 is a modulatory receptor of innate immune responses to cSSSI-related pathogens, and genetic variants in TLR10 are associated with protection against cSSSIs.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen Hasselt University, Belgium.
authors.forename: Mark H T
authors.initials: MH
authors.lastname: Stappers
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center.
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center.
authors.forename: Mihai
authors.initials: M
authors.lastname: Ioana
authors.affiliation: Bayer Healthcare Pharmaceuticals, Wuppertal, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Reimnitz
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen Department of Medical Microbiology and Infectious Diseases, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen Hasselt University, Belgium.
authors.forename: Inge C
authors.initials: IC
authors.lastname: Gyssens
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
mesh_terms: D000483:Alleles; D001441:Bacteroides fragilis; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D020022:Genetic Predisposition to Disease; D005838:Genotype; D060005:Genotyping Techniques; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D016015:Logistic Models; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D012867:Skin / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D012871:Skin Diseases / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D013211:Staphylococcus aureus; D051201:Toll-Like Receptor 10 / Q000235:genetics* / Q000378:metabolism
chemical_list: D015850:Interleukin-6; C475955:TLR10 protein, human; D051201:Toll-Like Receptor 10
keywords: Toll-like receptor 10; acute bacterial skin and skin structure infections; immunity, innate; polymorphism, single nucleotide; receptors, pattern recognition