Stappers Mark H T, Oosting Marije, Ioana Mihai, Reimnitz Peter, Mouton Johan W, Netea Mihai G, Gyssens Inge C, Joosten Leo A B
Department of Internal Medicine, Radboud University Medical Center Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen Hasselt University, Belgium.
Department of Internal Medicine, Radboud University Medical Center.
J Infect Dis. 2015 Nov 1;212(9):1491-9. doi: 10.1093/infdis/jiv229. Epub 2015 Apr 20.
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.
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.
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.
TLR10 is a modulatory receptor of innate immune responses to cSSSI-related pathogens, and genetic variants in TLR10 are associated with protection against cSSSIs.
Toll样受体（TLRs）在对复杂皮肤及皮肤结构感染（cSSSIs）的固有免疫反应中起核心作用，TLR10是已知的首个具有抑制功能的家族成员。本研究评估了TLR10在识别cSSSI相关病原体中的作用，以及TLR10基因变异是否影响对cSSSIs的易感性。
用抗TLR10抗体预孵育的人外周血单核细胞（PBMCs）和过表达TLRs的HEK-293细胞暴露于cSSSI病原体，通过酶联免疫吸附测定法测定细胞因子分泌。对318例cSSSI患者和328例健康对照进行TLR10中4个非同义单核苷酸多态性的基因分型，并通过体外刺激试验评估TLR10单核苷酸多态性的功能后果。
在存在TLR10中和抗体的情况下，用cSSSI病原体刺激PBMC显著增加白细胞介素6分泌。TLR10的过表达完全消除了HEK-293细胞对cSSSI病原体反应时TLR2诱导的白细胞介素8分泌。TLR10中的3个多态性，即I775L、I369L和N241H，与cSSSIs易感性降低相关。TLR10等位基因775L、369L或241H的存在增加了PBMC对cSSSI病原体反应时白细胞介素6的分泌。
TLR10是对cSSSI相关病原体固有免疫反应的调节受体，TLR10基因变异与预防cSSSIs有关。
