Human macrophage ATP7A is localized in the trans-Golgi apparatus, controls intracellular copper levels, and mediates macrophage responses to dermal wounds

Ha Won Kim, Qilin Chan, Scott E. Afton, Joseph A. Caruso, Barry Lai, Neal Lee Weintraub, Zhenyu Qin

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The copper transporter ATP7A has attracted significant attention since the discovery of its gene mutation leading to human Menkes disease. We previously reported that ATP7A is highly expressed in the human vasculature and identified a novel vascular function of ATP7A in modulation of the expression and activity of extracellular superoxide dismutase. We recently identified that ATP7A expression in THP-1 cells (a monocyte/macrophage model cell line) plays a role in the oxidation of low density lipoproteins, indicating that it is necessary to further investigate its expression and function in monocytes/macrophages. In the current study, we demonstrated the protein and mRNA expression of ATP7A in human peripheral blood mononuclear cell (PBMC)-derived macrophages and alveolar macrophages. ATP7A was strongly colocalized with the trans-Golgi apparatus in PBMC-derived macrophages. Intracellular copper, detected by synchrotron X-ray fluorescence microscopy, was found to be distributed to the nucleus and cytoplasm in human THP-1 cells. To confirm the role of endogenous ATP7A in macrophage copper homeostasis, we performed inductively coupled plasma mass spectrometry in murine peritoneal macrophages, which showed markedly increased intracellular copper levels in macrophages isolated from ATP7A-deficient mice versus control mice. Moreover, the role of ATP7A in regulating macrophage responses to dermal wounds was studied by introduction of control and ATP7A-downregulated THP-1 cells into dermal wounds of nude mice. Infiltration of THP-1 cells into thewounded area (detected by expression of human macrophage markers MAC2 and CD68) was reduced in response to downregulation of ATP7A, hinting decreased macrophage accumulation subsequent to dermal wounds. In summary, alongside our previous studies, these findings indicate that human macrophage ATP7A is localized in the trans-Golgi apparatus, regulates intracellular copper levels, and mediates macrophage responses to a dermal wound.

Original languageEnglish (US)
Pages (from-to)167-175
Number of pages9
JournalInflammation
Volume35
Issue number1
DOIs
StatePublished - Feb 1 2012

Fingerprint

Golgi Apparatus
Copper
Macrophages
Skin
Wounds and Injuries
Monocytes
Blood Cells
Down-Regulation
Menkes Kinky Hair Syndrome
Synchrotrons
Alveolar Macrophages
Genetic Association Studies
Peritoneal Macrophages
LDL Lipoproteins
Fluorescence Microscopy
Nude Mice
Superoxide Dismutase
Blood Vessels
Mass Spectrometry
Cytoplasm

Keywords

  • ATP7A
  • Copper
  • Macrophage

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Human macrophage ATP7A is localized in the trans-Golgi apparatus, controls intracellular copper levels, and mediates macrophage responses to dermal wounds. / Kim, Ha Won; Chan, Qilin; Afton, Scott E.; Caruso, Joseph A.; Lai, Barry; Weintraub, Neal Lee; Qin, Zhenyu.

In: Inflammation, Vol. 35, No. 1, 01.02.2012, p. 167-175.

Research output: Contribution to journalArticle

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