A Toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria
A Toll-like receptor 2-responsive lipid effector pathway protects mammals against skin infections with gram-positive bacteria
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DOI：
10.1128/iai.73.8.4512-4521.2005
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发表时间：
2005-08-01
影响因子：
3.1
通讯作者：
Beutler, B
中科院分区：
文献类型：
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作者：
Georgel, P;Crozat, K;Beutler, B
flake (flk) 是一种 N-乙基-N-亚硝基脲诱导的 C57BL/6 小鼠隐性种系突变，会损害化脓性链球菌和金黄色葡萄球菌皮肤感染的清除，这些革兰氏阳性病原体通过激活 Toll 样受体 2 (TLR2) 引发先天免疫反应（K. Takeda 和 S. Akira， 细胞。微生物。 5：143-153，2003）。定位克隆和测序表明，flk 是硬脂酰辅酶 A 去饱和酶 1 基因 (Scd1) 的一个新等位基因。片状纯合子显示出皮脂产生减少，并且无法合成单不饱和脂肪酸（MUFA）棕榈油酸酯（C-16.1）和油酸酯（C-18.1），这两种物质在体外对革兰氏阳性（但不是革兰氏阴性）生物体具有杀菌作用。然而，对金黄色葡萄球菌感染的小鼠进行皮内注射 MUFA 可以部分挽救片状表型，这表明可能需要额外的皮脂成分来改善细菌清除。在正常小鼠中，TLR2 信号传导强烈且特异性地诱导 Sed1（启动子中含有大量 NF-κ B 元件的基因）的转录。类似地，SCD1 基因是由人类皮脂细胞系中的 TLR2 信号传导诱导的。这些观察结果揭示了哺乳动物中存在受调节的、基于脂质的抗菌效应途径，并提出了治疗或预防革兰氏阳性菌感染的新方法。
flake (flk), an N-ethyl-N-nitrosourea-induced recessive germ line mutation of C57BL/6 mice, impairs the clearance of skin infections by Streptococcus pyogenes and Staphylococcus aureus, gram-positive pathogens that elicit innate immune responses by activating Toll-like receptor 2 (TLR2) (K. Takeda and S. Akira, Cell. Microbiol. 5:143-153, 2003). Positional cloning and sequencing revealed that flk is a novel allele of the stearoyl coenzyme A desaturase 1 gene (Scd1). flake homozygotes show reduced sebum production and are unable to synthesize the monounsaturated fatty acids (MUFA) palmitoleate (C-16.1) and oleate (C-18.1), both of which are bactericidal against gram-positive (but not gram-negative) organisms in vitro. However, intradermal MUFA administration to S. aureus-infected mice partially rescues the flake phenotype, which indicates that an additional component of the sebum may be required to improve bacterial clearance. In normal mice, transcription of Sed1-a gene with numerous NF-kappa B elements in its promoter-is strongly and specifically induced by TLR2 signaling. Similarly, the SCD1 gene is induced by TLR2 signaling in a human sebocyte cell line. These observations reveal the existence of a regulated, lipid-based antimicrobial effector pathway in mammals and suggest new approaches to the treatment or prevention of infections with gram-positive bacteria.