title: Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD.
abstract: 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.
authors.affiliation: Discipline of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: Rhys
authors.initials: R
authors.lastname: Hamon
authors.affiliation: Discipline of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: Claire C
authors.initials: CC
authors.lastname: Homan
authors.affiliation: Discipline of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.
authors.forename: Hai B
authors.initials: HB
authors.lastname: Tran
authors.affiliation: Department of Thoracic Medicine, Royal Adelaide Hospital, Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.
authors.forename: Violet R
authors.initials: VR
authors.lastname: Mukaro
authors.affiliation: Rheumatology Unit, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Lester
authors.affiliation: Discipline of Surgery, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: Eugene
authors.initials: E
authors.lastname: Roscioli
authors.affiliation: Discipline of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: Mariea D
authors.initials: MD
authors.lastname: Bosco
authors.affiliation: CRA-NUT, Roma, Italy.
authors.forename: Chiara M
authors.initials: CM
authors.lastname: Murgia
authors.affiliation: Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Melbourne, Victoria, Australia.
authors.forename: Margaret Leigh
authors.initials: ML
authors.lastname: Ackland
authors.affiliation: Department of Thoracic Medicine, Royal Adelaide Hospital, Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.
authors.forename: Hubertus P
authors.initials: HP
authors.lastname: Jersmann
authors.affiliation: Discipline of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: Carol
authors.initials: C
authors.lastname: Lang
authors.affiliation: Discipline of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Zalewski
authors.affiliation: Discipline of Medicine, University of Adelaide, The Queen Elizabeth Hospital, Woodville, South Australia, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Lung Research Laboratory, Hanson Institute, Adelaide, South Australia, Australia.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Hodge
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D004195:Disease Models, Animal; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D005029:Ethylenediamines; C403517:SLC39A1 protein, human; C498424:SLC39A2 protein, human; C017800:zinc-binding protein; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine