Babina Magda, Artuc Metin, Guhl Sven, Zuberbier Torsten
Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
Int J Mol Sci. 2017 Feb 28;18(3):525. doi: 10.3390/ijms18030525.
The Vitamin-A-metabolite retinoic acid (RA) acts as a master regulator of cellular programs. Mast cells (MCs) are primary effector cells of type-I-allergic reactions. We recently uncovered that human cutaneous MCs are enriched with RA network components over other skin cells. Yet, direct experimental evidence on the significance of the RA-MC axis is limited. Here, skin-derived cultured MCs were exposed to RA for seven days and investigated by flow-cytometry (BrdU incorporation, Annexin/PI, FcεRI), microscopy, RT-qPCR, histamine quantitation, protease activity, and degranulation assays. We found that while MC size and granularity remained unchanged, RA potently interfered with MC proliferation. Conversely, a modest survival-promoting effect from RA was noted. The granule constituents, histamine and tryptase, remained unaffected, while RA had a striking impact on MC chymase, whose expression dropped by gene and by peptidase activity. The newly uncovered performed similarly to chymase. Intriguingly, RA fostered allergic MC degranulation, in a way completely uncoupled from FcεRI expression, but it simultaneously restricted MRGPRX2-triggered histamine release in agreement with the reduced receptor expression. Vitamin-A-derived hormones thus re-shape skin-derived MCs numerically, phenotypically, and functionally. A general theme emerges, implying RA to skew MCs towards processes associated with (allergic) inflammation, while driving them away from the skin-imprinted MC ("MCs containing tryptase and chymase") signature (chymase, MRGPRX2). Collectively, MCs are substantial targets of the skin retinoid network.
维生素A代谢产物视黄酸（RA）是细胞程序的主要调节因子。肥大细胞（MCs）是I型过敏反应的主要效应细胞。我们最近发现，与其他皮肤细胞相比，人类皮肤MCs富含RA网络成分。然而，关于RA-MC轴重要性的直接实验证据有限。在这里，将皮肤来源的培养MCs暴露于RA中7天，并通过流式细胞术（BrdU掺入、膜联蛋白/碘化丙啶、FcεRI）、显微镜检查、RT-qPCR、组胺定量、蛋白酶活性和脱颗粒试验进行研究。我们发现，虽然MC的大小和颗粒度保持不变，但RA强烈干扰MC的增殖。相反，观察到RA有适度的促进存活的作用。颗粒成分组胺和类胰蛋白酶不受影响，而RA对MC糜蛋白酶有显著影响，其表达在基因水平和肽酶活性方面均下降。新发现的 与糜蛋白酶表现相似。有趣的是，RA促进了过敏性MC脱颗粒，其方式与FcεRI表达完全无关，但同时它限制了MRGPRX2触发的组胺释放，这与受体表达降低一致。因此，维生素A衍生的激素在数量、表型和功能上重塑了皮肤来源的MCs。一个普遍的主题出现了，这意味着RA使MCs倾向于与（过敏）炎症相关的过程，同时使它们远离皮肤印记的MC（“含有类胰蛋白酶和糜蛋白酶的MCs”）特征（糜蛋白酶、MRGPRX2）。总的来说，MCs是皮肤类视黄醇网络的重要靶点。
