Hu Frisk Jun Mei, Kjellén Lena, Kaler Stephen G, Pejler Gunnar, Öhrvik Helena
Department of Medical Biochemistry and Microbiology, Uppsala University, 75123 Uppsala, Sweden.
Section on Translational Neuroscience, Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and.
J Immunol. 2017 Dec 15;199(12):4132-4141. doi: 10.4049/jimmunol.1700786. Epub 2017 Nov 10.
Copper has previously been implicated in the regulation of immune responses, but the impact of this metal on mast cells is poorly understood. In this article, we address this issue and show that copper starvation of mast cells causes increased granule maturation, as indicated by higher proteoglycan content, stronger metachromatic staining, and altered ultrastructure in comparison with nontreated cells, whereas copper overload has the opposite effects. In contrast, copper status did not impact storage of histamine in mast cells, nor did alterations in copper levels affect the ability of mast cells to degranulate in response to IgER cross-linking. A striking finding was decreased tryptase content in mast cells with copper overload, whereas copper starvation increased tryptase content. These effects were associated with corresponding shifts in tryptase mRNA levels, suggesting that copper affects tryptase gene regulation. Mechanistically, we found that alterations in copper status affected the expression of microphthalmia-associated transcription factor, a transcription factor critical for driving tryptase expression. We also found evidence supporting the concept that the effects on microphthalmia-associated transcription factor are dependent on copper-mediated modulation of MAPK signaling. Finally, we show that, in MEDNIK syndrome, a condition associated with low copper levels and a hyperallergenic skin phenotype, including pruritis and dermatitis, the number of tryptase-positive mast cells is increased. Taken together, our findings reveal a hitherto unrecognized role for copper in the regulation of mast cell gene expression and maturation.
此前已有研究表明铜参与免疫反应的调节，但这种金属对肥大细胞的影响却鲜为人知。在本文中，我们探讨了这一问题，并发现肥大细胞缺铜会导致颗粒成熟增加，与未处理的细胞相比，蛋白聚糖含量更高、异染性染色更强以及超微结构改变均表明了这一点，而铜过载则产生相反的效果。相比之下，铜状态对肥大细胞中组胺的储存没有影响，铜水平的改变也不会影响肥大细胞对IgER交联反应的脱颗粒能力。一个惊人的发现是，铜过载的肥大细胞中类胰蛋白酶含量降低，而缺铜则会增加类胰蛋白酶含量。这些效应与类胰蛋白酶mRNA水平的相应变化相关，表明铜会影响类胰蛋白酶基因的调控。从机制上讲，我们发现铜状态的改变会影响小眼相关转录因子的表达，小眼相关转录因子是驱动类胰蛋白酶表达的关键转录因子。我们还发现有证据支持这样的观点，即对小眼相关转录因子的影响依赖于铜介导的丝裂原活化蛋白激酶（MAPK）信号通路的调节。最后，我们发现，在MEDNIK综合征（一种与低铜水平和包括瘙痒症和皮炎在内的高敏皮肤表型相关的疾病）中，类胰蛋白酶阳性肥大细胞的数量增加。综上所述，我们的研究结果揭示了铜在肥大细胞基因表达和成熟调节中迄今未被认识的作用。
