The reduced susceptibility of mouse keratinocytes to retinoic acid may be involved in the keratinization of oral and esophageal mucosal epithelium.
The reduced susceptibility of mouse keratinocytes to retinoic acid may be involved in the keratinization of oral and esophageal mucosal epithelium.
复制标题
小鼠角质形成细胞对视黄酸的敏感性降低可能与口腔和食管粘膜上皮的角化有关。
DOI：
10.1007/s00418-020-01845-1
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发表时间：
2019
影响因子：
2.3
通讯作者：
Inai T
中科院分区：
文献类型：
--
作者：
Miyazono S;Otani T;Ogata K;Kitagawa N;Iida H;Inai Y;Matsuura T;Inai T
角质形成细胞吸收血清来源的视黄醇（维生素A）并将其代谢为全反式视黄酸（atRA），后者与核视黄酸受体（RAR）结合。我们之前报道过血清影响角质细胞分化和功能；即，它抑制角化，降低loricrin （LOR）和CLDN (CLDN) 1的表达，增加角蛋白(K) 4和CLDN4的水平，降低小鼠角化细胞（COCA）三维（3D）培养的细胞旁通透性。相反，RAR抑制逆转了这些变化。在这里，我们的目的是研究atRA是否发挥与血清相同的作用，以及它是否参与动物物种间口腔黏膜角化的差异。猪口腔黏膜角化细胞，在体内形成非角化上皮，在3D培养中建立角化上皮。在COCA 3D培养中，小鼠和猪血清均以0.1%的浓度诱导非角化上皮。atRA引起的变化与血清相同，但其有效浓度不同。atRA分别在0.1 nM和1 nM抑制猪或人角化细胞和COCA的角化。此外，atRA在细胞质中上调了CLDN7，但在细胞-细胞接触中没有上调。这些atra诱导的变化被RAR抑制逆转。结果表明，血清诱导的变化可能是由于血清来源的atRA的作用，小鼠角化细胞比猪和人角化细胞需要更高的atRA浓度来抑制角化。我们认为，小鼠角化细胞对atRA的敏感性较低，而不是视黄醇浓度较低，可能是小鼠口腔黏膜上皮角化的原因。
Keratinocytes take up serum-derived retinol (vitamin A) and metabolize it to all-trans-retinoic acid (atRA), which binds to the nuclear retinoic acid receptor (RAR). We previously reported that serum-affected keratinocyte differentiation and function; namely, it inhibited keratinization, decreased loricrin (LOR) and claudin (CLDN) 1 expression, increased keratin (K) 4 and CLDN4 levels, and reduced paracellular permeability in three-dimensional (3D) cultures of mouse keratinocytes (COCA). Contrarily, RAR inhibition reversed these changes. Here, we aimed to examine whether atRA exerted the same effects as serum, and whether it was involved in the differential oral mucosa keratinization among animal species. Porcine oral mucosal keratinocytes, which form non-keratinized epithelium in vivo, established keratinized epithelium in 3D cultures. Both mouse and porcine sera induced non-keratinized epithelium at 0.1% in COCA 3D cultures. Although atRA caused the same changes as serum, its effective concentration differed. atRA inhibited keratinization at 0.1 nM and 1 nM in porcine or human keratinocytes and COCA, respectively. Furthermore, atRA upregulated CLDN7 in the cytoplasm but not in cell–cell contacts. These atRA-induced changes were reverted by RAR inhibition. The results indicate that serum-induced changes are probably due to the effect of serum-derived atRA, and that mouse keratinocytes require higher atRA concentrations to suppress keratinization than porcine and human keratinocytes. We propose that the lower susceptibility of mouse keratinocytes to atRA, rather than a lower retinol concentration, is a possible reason for the keratinization of mouse oral mucosal epithelium.