Laboratorio de Neuroinmunología, Fundación Ciencia & Vida, Santiago, Chile.
Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile.
Biol Res. 2021 Oct 28;54(1):35. doi: 10.1186/s40659-021-00357-z.
Urushiols are pro-electrophilic haptens that cause severe contact dermatitis mediated by CD8 effector T-cells and downregulated by CD4 T-cells. However, the molecular mechanism by which urushiols stimulate innate immunity in the initial stages of this allergic reaction is poorly understood. Here we explore the sub-cellular mechanisms by which urushiols initiate the allergic response.
Electron microscopy observations of mouse ears exposed to litreol (3-n-pentadecyl-10-enyl-catechol]) showed keratinocytes containing swollen mitochondria with round electron-dense inclusion bodies in the matrix. Biochemical analyses of sub-mitochondrial fractions revealed an inhibitory effect of urushiols on electron flow through the mitochondrial respiratory chain, which requires both the aliphatic and catecholic moieties of these allergens. Moreover, urushiols extracted from poison ivy/oak (mixtures of 3-n-pentadecyl-8,11,13 enyl/3-n-heptadecyl-8,11 enyl catechol) exerted a higher inhibitory effect on mitochondrial respiration than did pentadecyl catechol or litreol, indicating that the higher number of unsaturations in the aliphatic chain, stronger the allergenicity of urushiols. Furthermore, the analysis of radioactive proteins isolated from mitochondria incubated with H-litreol, indicated that this urushiol was bound to cytochrome c. According to the proximity of cytochromes c and b, functional evidence indicated the site of electron flow inhibition was within complex III, in between cytochromes b (cyt b) and b (cyt b).
Our data provide functional and molecular evidence indicating that the interruption of the mitochondrial electron transport chain constitutes an important mechanism by which urushiols initiates the allergic response. Thus, mitochondria may constitute a source of cellular targets for generating neoantigens involved in the T-cell mediated allergy induced by urushiols.
漆酚是亲电半抗原，可引起 CD8 效应 T 细胞介导的严重接触性皮炎，并被 CD4 T 细胞下调。然而，漆酚在这种过敏反应的初始阶段刺激固有免疫的分子机制尚不清楚。在这里，我们探讨了漆酚引发过敏反应的亚细胞机制。
用电子显微镜观察小鼠耳朵暴露于漆酚（3-n-戊基-10-烯基儿茶酚）后，发现角质细胞含有肿胀的线粒体，基质中存在圆形电子致密内含物。对亚线粒体部分的生化分析表明，漆酚抑制电子通过线粒体呼吸链的流动，这需要这些过敏原的脂肪族和儿茶酚部分。此外，从毒藤/毒橡木（3-n-戊基-8,11,13 烯基/3-n-十七基-8,11 烯基儿茶酚混合物）中提取的漆酚对线粒体呼吸的抑制作用强于十五烷基儿茶酚或漆酚，表明脂肪链中的不饱和程度越高，漆酚的致敏性越强。此外，从与 H-漆酚孵育的线粒体中分离出的放射性蛋白质分析表明，这种漆酚与细胞色素 c 结合。根据细胞色素 c 和 b 的接近程度，功能证据表明电子流抑制的部位位于复合物 III 内，细胞色素 b（cyt b）和 b（cyt b）之间。
我们的数据提供了功能和分子证据，表明线粒体电子传递链的中断是漆酚引发过敏反应的一个重要机制。因此，线粒体可能构成产生与漆酚诱导的 T 细胞介导过敏反应相关的新抗原的细胞靶标来源。
