Department of Dermatology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
Nat Immunol. 2010 Sep;11(9):814-9. doi: 10.1038/ni.1919. Epub 2010 Aug 15.
Allergies to nickel (Ni(2+)) are the most frequent cause of contact hypersensitivity (CHS) in industrialized countries. The efficient development of CHS requires both a T lymphocyte-specific signal and a proinflammatory signal. Here we show that Ni(2+) triggered an inflammatory response by directly activating human Toll-like receptor 4 (TLR4). Ni(2+)-induced TLR4 activation was species-specific, as mouse TLR4 could not generate this response. Studies with mutant TLR4 proteins revealed that the non-conserved histidines 456 and 458 of human TLR4 are required for activation by Ni(2+) but not by the natural ligand lipopolysaccharide. Accordingly, transgenic expression of human TLR4 in TLR4-deficient mice allowed efficient sensitization to Ni(2+) and elicitation of CHS. Our data implicate site-specific human TLR4 inhibition as a potential strategy for therapeutic intervention in CHS that would not affect vital immune responses.
镍（Ni(2+)）过敏是工业化国家中接触性超敏反应（CHS）最常见的原因。CHS 的有效发展既需要 T 淋巴细胞特异性信号，也需要促炎信号。在这里，我们表明 Ni(2+) 通过直接激活人 Toll 样受体 4（TLR4）引发炎症反应。Ni(2+)-诱导的 TLR4 激活具有种属特异性，因为鼠 TLR4 不能产生这种反应。用突变 TLR4 蛋白进行的研究表明，人 TLR4 中不保守的组氨酸 456 和 458 对于 Ni(2+)的激活，但不是对于天然配体脂多糖的激活是必需的。因此，在 TLR4 缺陷型小鼠中转基因表达人 TLR4 可有效致敏 Ni(2+)并引发 CHS。我们的数据表明，针对特定部位的人 TLR4 抑制可能是治疗 CHS 的一种潜在策略，而不会影响重要的免疫反应。
