Wakabayashi Masato, Yoshioka Takeshi, Higashino Kenichi, Numata Yoshito, Igarashi Yasuyuki, Kihara Akio
Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo 001-0021, Japan; Laboratory of Biochemistry, Graduate School of Life Science, Hokkaido University, Sapporo 060-0812, Japan.
Shionogi Innovation Center for Drug Discovery, Discovery Research Laboratory for Innovative Frontier Medicines, Shionogi & Co., Ltd., Sapporo 001-0021, Japan.
J Dermatol Sci. 2017 Mar;85(3):186-196. doi: 10.1016/j.jdermsci.2016.12.013. Epub 2016 Dec 15.
Olmsted syndrome (OS) is a congenital dermatosis characterized by palmoplantar keratoderma and periorificial keratotic plaque. TRPV3 (transient receptor potential vanilloid subtype 3) encodes a thermosensitive Ca channel and is the causative gene of OS. However, the molecular mechanism that causes the pathological development of OS is unclear.
We aimed to investigate the molecular mechanisms underlying OS pathology from the perspective of lipid metabolism.
Comprehensive lipidomics and microarray analyses were conducted on tissue samples from a non-lesional skin area of OS model rats (Ht rats) and from wild type (WT) rats as the control.
Infiltration of leukocytes such as eosinophils and neutrophils and an increase in the fibrotic region were detected in the unaffected skin area of Ht rats compared with the WT rats. Among about 600 lipid species examined, the levels of 15-lipoxygenase (LOX) metabolites, the precursors of anti-inflammatory and pro-resolving lipid mediators, and dihydroceramides decreased by ≥16-fold in Ht rats compared with WT rats. Consistent with the decreases in the 15-LOX metabolites, expression levels of the genes that encode the 15-LOXs, Alox15 and Alox15b, were largely reduced. Conversely, increased expression levels were detected of Il36b, Ccl20, Cxcl1, and Cxcl2, which encode cytokines/chemokines, and S100a8 and S100a9, which encode the Ca binding proteins that are implicated in epidermal proliferation.
The pro-inflammatory state in the unaffected skin of Ht rats caused by decreases in 15-LOX metabolites and increases in cytokines/chemokines may contribute to the pathogenesis of OS.
奥姆斯特德综合征（OS）是一种先天性皮肤病，其特征为掌跖角化病和口周角化性斑块。瞬时受体电位香草酸亚型3（TRPV3）编码一种热敏钙通道，是OS的致病基因。然而，导致OS病理发展的分子机制尚不清楚。
我们旨在从脂质代谢的角度研究OS病理的分子机制。
对OS模型大鼠（Ht大鼠）非病变皮肤区域和作为对照的野生型（WT）大鼠的组织样本进行综合脂质组学和微阵列分析。
与WT大鼠相比，在Ht大鼠未受影响的皮肤区域检测到嗜酸性粒细胞和中性粒细胞等白细胞浸润以及纤维化区域增加。在所检测的约600种脂质种类中，与WT大鼠相比，Ht大鼠中15-脂氧合酶（LOX）代谢产物（抗炎和促消退脂质介质的前体）和二氢神经酰胺的水平降低了≥16倍。与15-LOX代谢产物的减少一致，编码15-LOXs的基因Alox15和Alox15b的表达水平大幅降低。相反，检测到编码细胞因子/趋化因子的Il36b、Ccl20、Cxcl1和Cxcl2以及编码与表皮增殖有关的钙结合蛋白的S100a8和S100a9的表达水平增加。
15-LOX代谢产物减少和细胞因子/趋化因子增加导致Ht大鼠未受影响皮肤中的促炎状态，这可能有助于OS的发病机制。
