对结节性痒疹的单细胞分析表明，免疫-基质细胞相互作用驱动成纤维细胞反应，并用 nemolizumab 逆转。
Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab.
机构信息
Department of Dermatology, University of Michigan, Ann Arbor, Mich.
Department of Dermatology, University of Michigan, Ann Arbor, Mich; Department of Biostatistics, University of Michigan, Ann Arbor, Mich; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Mich.
出版信息
J Allergy Clin Immunol. 2024 Jan;153(1):146-160. doi: 10.1016/j.jaci.2023.07.005. Epub 2023 Jul 26.
BACKGROUND
Prurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk. Neuroimmune dysregulation and chronic scratching are believed to both induce and maintain the characteristic lesions.
OBJECTIVES
This study sought to provide a comprehensive view of the molecular pathogenesis of PN at the single-cell level to identify and outline key pathologic processes and the cell types involved. Features that distinguish PN skin from the skin of patients with atopic dermatitis were of particular interest. We further aimed to determine the impact of the IL31RA antagonist, nemolizumab, and its specificity at the single-cell level.
METHODS
Single-cell RNA-sequencing of skin from 15 healthy donors and nonlesional and lesional skin from 6 patients each with PN and atopic dermatitis, combined with spatial-sequencing using the 10x Visium platform. Integration with bulk RNA-sequencing data from patients treated with nemolizumab.
RESULTS
This study demonstrates that PN is an inflammatory skin disease characterized by both keratinocyte proliferation and activation of profibrotic responses. This study also demonstrates that the COL11A1 fibroblast subset is a major contributor to fibrosis and is predominantly found in the papillary dermis of PN skin. Activation of fibrotic responses is the main distinguishing feature between PN and atopic dermatitis skin. This study further shows the broad effect of nemolizumab on PN cell types, with a prominent effect driving COL11A1 fibroblast and keratinocyte responses toward normal.
CONCLUSIONS
This study provides a high-resolution characterization of the cell types and cellular processes activated in PN skin, establishing PN as a chronic fibrotic inflammatory skin disease. It further demonstrates the broad effect of nemolizumab on pathological processes in PN skin.
背景
结节性痒疹（PN）是一种慢性神经免疫性皮肤病，其特征为四肢和躯干双侧分布的瘙痒性角化过度结节。神经免疫失调和慢性搔抓被认为既可以诱导也可以维持其特征性病变。
目的
本研究旨在从单细胞水平全面了解 PN 的分子发病机制，以确定和概述关键的病理过程和涉及的细胞类型。与特应性皮炎患者皮肤相比，能够区分 PN 皮肤的特征尤其受到关注。我们还旨在确定 IL31RA 拮抗剂 nemolizumab 及其在单细胞水平的特异性的影响。
方法
对 15 名健康供体的皮肤、6 名每个患有 PN 和特应性皮炎的患者的非皮损和皮损皮肤进行单细胞 RNA 测序，并结合使用 10x Visium 平台的空间测序。与接受 nemolizumab 治疗的患者的批量 RNA 测序数据进行整合。
结果
本研究表明，PN 是一种炎症性皮肤病，其特征为角质形成细胞增殖和促纤维化反应的激活。本研究还表明，COL11A1 成纤维细胞亚群是纤维化的主要贡献者，主要存在于 PN 皮肤的乳头真皮中。纤维化反应的激活是 PN 和特应性皮炎皮肤之间的主要区别特征。本研究进一步表明，nemolizumab 对 PN 细胞类型具有广泛的影响，主要作用是驱动 COL11A1 成纤维细胞和角质形成细胞反应向正常化。
结论
本研究提供了对 PN 皮肤中激活的细胞类型和细胞过程的高分辨率描述，将 PN 确立为一种慢性纤维化炎症性皮肤病。它进一步证明了 nemolizumab 对 PN 皮肤病理过程的广泛影响。
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