Copper Regulates Maturation and Expression of an MITF:Tryptase Axis in Mast Cells

Abstract

Copper has previously been implicated in the regulation of immune responses, but the impact of this metal on mast cells is poorly understood. Here, 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 non-treated cells, whereas copper overload has 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 IgE receptor crosslinking. 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 Mitf, a transcription factor critical for driving tryptase expression. We also found evidence supporting the concept that the effects on Mitf 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 hyper-allergenic 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 regulation of mast cell gene expression and maturation.

Mitogen-Activated Protein Kinase Signaling Regulates Proteoglycan Composition of Mast Cell Secretory Granules

“…As shown in Figure 1 B and in agreement with observations made in a previous study in Ref. ( 27 ), incubation of BMMCs with PD98059 caused a profound increase in the metachromatic staining properties of the BMMCs. This effect was evident as early as after 24 h and was clearly visible also after long-term exposure to the MEK1/2 inhibitor (Figure 1 B).…”

“…As depicted in Figure 6 A, PD98059 treatment of BMMCs caused a robust increase in the amount of stored trypsin-like activity, a finding that is in agreement with an observation in a previous study in Ref. ( 27 ). This was seen after 3 days of culture and was more pronounced after 5–7 days.…”

“…The exact mechanism behind the upregulated expression of serglycin after interference with MAPK signaling is not entirely clear. However, a previous study suggested that MEK1/2 inhibition causes upregulated expression of the transcription factor MITF ( 27 ). MITF is a major transcription factor regulating MC development, having a key role in promoting multiple features of MCs including expression of MC proteases ( 33 ).…”

Copper (II) Ions Activate Ligand-Independent Receptor Tyrosine Kinase (RTK) Signaling Pathway

“…It has been reported that CD 147 autocorrelation induced by copper targeting is a new tumor therapy strategy [15]. Copper has been involved in the regulation of the immune response and plays an essential role in regulating gene expression and the maturation of fine hypertrophic cells [16]. Copper has excellent antibacterial properties, and it is not easy for bacterial resistance to develop in response to it.…”

Mouse Tryptase Gene Expression is Coordinately Regulated by GATA1 and GATA2 in Bone Marrow-Derived Mast Cells

“…Regarding the Tpsb2 activation, polyomavirus enhancer binding protein 2 (PEBP2) physically interacts with MITF and synergistically activates the Tpsb2 gene transcription [13]. The MITF mRNA and protein levels were recently shown to be reduced upon copper-mediated phosphorylation of MEK1/2 [16].…”