Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Adaptive Immunity Research Unit, GlaxoSmithKline Medicine's Research Centre, Stevenage, United Kingdom.
J Clin Invest. 2020 Sep 1;130(9):4798-4810. doi: 10.1172/JCI132987.
The biology of harlequin ichthyosis (HI), a devastating skin disorder caused by loss-of-function mutations in the gene ABCA12, is poorly understood, and to date, no satisfactory treatment has been developed. We sought to investigate pathomechanisms of HI that could lead to the identification of new treatments for improving patients' quality of life. In this study, RNA-Seq and functional assays were performed to define the effects of loss of ABCA12 using HI patient skin samples and an engineered CRISPR/Cas9 ABCA12 KO cell line. The HI living skin equivalent (3D model) recapitulated the HI skin phenotype. The cytokines IL-36α and IL-36γ were upregulated in HI skin, whereas the innate immune inhibitor IL-37 was strongly downregulated. We also identified STAT1 and its downstream target inducible nitric oxide synthase (NOS2) as being upregulated in the in vitro HI 3D model and HI patient skin samples. Inhibition of NOS2 using the inhibitor 1400W or the JAK inhibitor tofacitinib dramatically improved the in vitro HI phenotype by restoring the lipid barrier in the HI 3D model. Our study has identified dysregulated pathways in HI skin that are feasible therapeutic targets.
遗传性先天性鱼鳞病样红皮病（HI）是一种严重的皮肤疾病，由 ABCA12 基因功能丧失性突变引起，其发病机制目前尚不清楚，也尚未研发出有效的治疗方法。本研究旨在探讨 HI 的发病机制，以期找到改善患者生活质量的新疗法。本研究通过 HI 患者皮肤样本和经基因编辑的 ABCA12 KO 细胞系，采用 RNA-Seq 和功能测定方法，研究了 ABCA12 缺失的影响。HI 皮肤等效物（3D 模型）重现了 HI 皮肤表型。在 HI 皮肤中，细胞因子 IL-36α 和 IL-36γ 上调，而先天免疫抑制剂 IL-37 则明显下调。我们还发现，在体外 HI 3D 模型和 HI 患者皮肤样本中，STAT1 及其下游靶基因诱导型一氧化氮合酶（NOS2）上调。NOS2 抑制剂 1400W 或 JAK 抑制剂托法替尼抑制 NOS2，可通过恢复 HI 3D 模型中的脂质屏障，显著改善体外 HI 表型。本研究鉴定了 HI 皮肤中失调的信号通路，这些通路可能是可行的治疗靶点。
