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Copper Regulates Maturation and Expression of an MITF: Tryptase Axis in Mast Cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Translat Neurosci, Mol Med Branch, NIH, Bethesda, MD 20892 USA.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, S-75007 Uppsala, Sweden.ORCID iD: 0000-0002-6779-391x
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2017 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 199, no 12, p. 4132-4141Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 199, no 12, p. 4132-4141
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-340995DOI: 10.4049/jimmunol.1700786ISI: 000417018100021PubMedID: 29127151OAI: oai:DiVA.org:uu-340995DiVA, id: diva2:1180459
Funder
Swedish Research CouncilSwedish Cancer SocietySwedish Heart Lung FoundationTorsten Söderbergs stiftelseMagnus Bergvall FoundationÅke Wiberg FoundationNIH (National Institute of Health), Z01 HD008768.; Z01 HD008927Available from: 2018-02-05 Created: 2018-02-05 Last updated: 2018-03-02Bibliographically approved

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Hu Frisk, Jun MeiKjellén, LenaPejler, GunnarÖhrvik, Helena

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