炎症致特应性皮炎皮肤屏障功能破坏的机制和干预策略

IL-31 was an important inflammatory factor in atopic dermatitis(AD), which led to pruritus and disrupted skin barrier function. The effect of Staphylococcal Enterotoxin（SE）on IL-31 was paradoxical: it stimulated CLA+T cells to produce much IL-31 in vitro while it also down-regulated antimicrobial peptide(AMP) in keratinocytes(KCs), which paralleled to mast cell-dependent IL-31 expression. CLA+ T cells targeted therapy improved AD by reducing CLA+ T cells in lesional skin, but CLA+ T cells in peripheral blood increased. Then the expression of IL-31 remained unknown and the up-regulation of IL-31 might be a risk factor of AD relapse. Our previous research verified that lidocaine could promote the differentiation of regulatory T cells and up-regulate FLG expression, but the mechanism should be a further research. So our aims of the research are as follows: ①We aim to clarify the relationship between the production of IL-31 in SE-stimulated CLA+T cells and that in mast cells. The association between CLA+ T cells, which are both in blood and lesional skin, and the expression of IL-31 will also be detected.②We plan to verify if lidocaine up-regulates FLG expression via inhibiting the expression of MHCII on KCs or reducing the upstream production of IL-31. ③We intend to explore the role of lidocaine in Na+ influx or IL-31RA-TRPV1 mediated Ca2+ influx in KCs , which uncovers the mechanism of its regulation of pruritus .

IL-31是致特应性皮炎（AD）瘙痒及皮肤屏障功能破坏的重要炎症因子。金葡菌外毒素（SE）可诱导CLA+T细胞分泌IL-31，本课题组发现SE下调抗菌肽（AMP），而AMP与肥大细胞分泌IL-31正相关，那么SE对IL-31的最终作用是上调还是下调？靶向治疗下调皮损中CLA+T细胞数量可改善AD，但致外周血CLA+T细胞增多，那么外周血IL-31是否上调，从而增加AD复发风险？本课题组发现利多卡因促进Treg分化并上调FLG表达，但机制仍待深入研究。本研究拟①探究SE刺激下CLA+T细胞和肥大细胞分泌IL-31水平，揭示血液及皮损CLA+T细胞数量和IL-31水平与疾病的相关性；②明确利多卡因是直接抑制KCs表面MHCII高表达或间接抑制上游IL-31释放，从而上调FLG表达；③探索利多卡因干预前后KCs中Na+内流及IL-31RA-TRPV1中Ca2+内流的差异，明确其对瘙痒影响的机制。

本课题组发现利多卡因通过阻断NaV1.8阳性感觉神经元可在患者和小鼠模型上同时发挥抗瘙痒及抗炎症的作用，仅失活NaV1.8阳性感觉神经元就能达到抗炎及抗瘙痒的作用，但损毁TRPV1阳性伤害性感觉神经元仅能止痒但不能抗炎，提示了特应性皮炎（Atopic Dermatitis, AD）中皮肤炎症及瘙痒的不同的感觉神经元调控模式。此外，利多卡因抑制感觉神经元活性依赖的降钙素基因相关肽（Calcitonin Gene Related Peptide，CGRP）释放从而发挥抗炎和抗瘙痒作用。本研究揭示了NaV1.8阳性感觉神经元在AD发病中的重要作用，并且利多卡因可作为潜在的作用于AD神经免疫环路的抗瘙痒及抗炎症的治疗策略。该研究目前正在投稿中。本项目组通过对1008例AD患者24项临床体征在各年龄阶段的分布研究，发现3项对于AD早期诊断具有潜在应用价值的临床体征；在此基础上建立中国婴儿与儿童的AD诊断标准，发表于国际皮肤病学权威期刊《JEADV》。项目组长期致力于AD的临床与基础研究，负责人作为第一完成人获得2020年华夏医学科技奖一等奖；2018年中华医学科技奖二等奖；2017年度（第十六届）上海医学科技奖二等奖。本项目共计发表标注本项目的SCI论文14篇。举办全国性学术会议2次，参加国内学术交流10次以上。培养已毕业博士研究生5名，已毕业硕士研究生2名。