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Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD

Hamon,R, Homan,CC, Tran,HB, Mukaro,VR, Lester,SE, Roscioli,E, Bosco,MD, Murgia,CM, Ackland,ML, Jersmann,HP, Lang,C, Zalewski,PD and Hodge,SJ 2014, Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD, PLoS one, vol. 9, no. 10, pp. 1-9, doi: 10.1371/journal.pone.0110056.

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Title Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD
Author(s) Hamon,R
Homan,CC
Tran,HB
Mukaro,VR
Lester,SE
Roscioli,E
Bosco,MD
Murgia,CM
Ackland,MLORCID iD for Ackland,ML orcid.org/0000-0002-7474-6556
Jersmann,HP
Lang,C
Zalewski,PD
Hodge,SJ
Journal name PLoS one
Volume number 9
Issue number 10
Start page 1
End page 9
Publisher Public Library of Science
Place of publication San Francisco, CA
Publication date 2014-10
ISSN 1932-6203
Keyword(s) Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
OBSTRUCTIVE PULMONARY-DISEASE
ALLERGIC AIRWAY INFLAMMATION
NF-KAPPA-B
ALVEOLAR MACROPHAGES
EPITHELIAL-CELLS
HOST-DEFENSE
MURINE MODEL
LUNG
EXPRESSION
HOMEOSTASIS
Summary Our previous studies have shown that nutritional zinc restriction exacerbates airway inflammation accompanied by an increase in caspase-3 activation and an accumulation of apoptotic epithelial cells in the bronchioles of the mice. Normally, apoptotic cells are rapidly cleared by macrophage efferocytosis, limiting any secondary necrosis and inflammation. We therefore hypothesized that zinc deficiency is not only pro-apoptotic but also impairs macrophage efferocytosis. Impaired efferocytic clearance of apoptotic epithelial cells by alveolar macrophages occurs in chronic obstructive pulmonary disease (COPD), cigarette-smoking and other lung inflammatory diseases. We now show that zinc is a factor in impaired macrophage efferocytosis in COPD. Concentrations of zinc were significantly reduced in the supernatant of bronchoalveolar lavage fluid of patients with COPD who were current smokers, compared to healthy controls, smokers or COPD patients not actively smoking. Lavage zinc was positively correlated with AM efferocytosis and there was decreased efferocytosis in macrophages depleted of Zn in vitro by treatment with the membrane-permeable zinc chelator TPEN. Organ and cell Zn homeostasis are mediated by two families of membrane ZIP and ZnT proteins. Macrophages of mice null for ZIP1 had significantly lower intracellular zinc and efferocytosis capability, suggesting ZIP1 may play an important role. We investigated further using the human THP-1 derived macrophage cell line, with and without zinc chelation by TPEN to mimic zinc deficiency. There was no change in ZIP1 mRNA levels by TPEN but a significant 3-fold increase in expression of another influx transporter ZIP2, consistent with a role for ZIP2 in maintaining macrophage Zn levels. Both ZIP1 and ZIP2 proteins were localized to the plasma membrane and cytoplasm in normal human lung alveolar macrophages. We propose that zinc homeostasis in macrophages involves the coordinated action of ZIP1 and ZIP2 transporters responding differently to zinc deficiency signals and that these play important roles in macrophage efferocytosis.
Language eng
DOI 10.1371/journal.pone.0110056
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 929999 Health not elsewhere classified
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2014, Public Library of Science
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30070080

Document type: Journal Article
Collections: School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.