title: Human TLR10 is an anti-inflammatory pattern-recognition receptor.
abstract: Toll-like receptor (TLR)10 is the only pattern-recognition receptor without known ligand specificity and biological function. We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects. Blocking TLR10 by antagonistic antibodies enhanced proinflammatory cytokine production, including IL-1β, specifically after exposure to TLR2 ligands. Blocking TLR10 after stimulation of peripheral blood mononuclear cells with pam3CSK4 (Pam3Cys) led to production of 2,065 ± 106 pg/mL IL-1β (mean ± SEM) in comparison with 1,043 ± 51 pg/mL IL-1β after addition of nonspecific IgG antibodies. Several mechanisms mediate the modulatory effects of TLR10: on the one hand, cotransfection in human cell lines showed that TLR10 acts as an inhibitory receptor when forming heterodimers with TLR2; on the other hand, cross-linking experiments showed specific induction of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra, 16 ± 1.7 ng/mL, mean ± SEM). After cross-linking anti-TLR10 antibody, no production of IL-1β and other proinflammatory cytokines could be found. Furthermore, individuals bearing TLR10 polymorphisms displayed an increased capacity to produce IL-1β, TNF-α, and IL-6 upon ligation of TLR2, in a gene-dose-dependent manner. The modulatory effects of TLR10 are complex, involving at least several mechanisms: there is competition for ligands or for the formation of heterodimer receptors with TLR2, as well as PI3K/Akt-mediated induction of the anti-inflammatory cytokine IL-1Ra. Finally, transgenic mice expressing human TLR10 produced fewer cytokines when challenged with a TLR2 agonist. In conclusion, to our knowledge we demonstrate for the first time that TLR10 is a modulatory pattern-recognition receptor with mainly inhibitory properties.
authors.affiliation: Department of Internal Medicine.
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.affiliation: Department of Internal Medicine.
authors.forename: Shih-Chin
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Department of Immune Therapeutics, Merck Research Laboratories, Oss 5342 CC, The Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Bolscher
authors.affiliation: Department of Internal Medicine.
authors.forename: Rachel
authors.initials: R
authors.lastname: Vestering-Stenger
authors.affiliation: Department of Internal Medicine.
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.affiliation: Department of Internal Medicine.
authors.forename: Ineke C
authors.initials: IC
authors.lastname: Verschueren
authors.affiliation: Department of Human Genetics.
authors.forename: Peer
authors.initials: P
authors.lastname: Arts
authors.affiliation: Department of Immune Therapeutics, Merck Research Laboratories, Oss 5342 CC, The Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Garritsen
authors.affiliation: Department of Immune Therapeutics, Merck Research Laboratories, Oss 5342 CC, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Eenennaam
authors.affiliation: Department of Microbiology, and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sturm
authors.affiliation: Department of Internal Medicine.
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.affiliation: Department of Human Genetics.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Tumour Immunology, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands; and.
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.affiliation: Department of Internal Medicine.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: Department of Internal Medicine.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Internal Medicine, leo.joosten@radboudumc.nl.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D051192:Receptors, Pattern Recognition / Q000378:metabolism*; D015398:Signal Transduction; D051201:Toll-Like Receptor 10 / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D051192:Receptors, Pattern Recognition; C475955:TLR10 protein, human; C495342:TLR2 protein, human; D051201:Toll-Like Receptor 10; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha
keywords: SNPs; TLR10; cytokines; immunology