Metallothionein 3 Controls the Phenotype and Metabolic Programming of Alternatively Activated Macrophages
Identifieur interne : 000588 ( Pmc/Checkpoint ); précédent : 000587; suivant : 000589Metallothionein 3 Controls the Phenotype and Metabolic Programming of Alternatively Activated Macrophages
Auteurs : Debabrata Chowdhury [États-Unis] ; Hani Alrefai [États-Unis] ; Julio A. Landero Figueroa [États-Unis] ; Kathleen Candor [États-Unis] ; Aleksey Porollo [États-Unis] ; Roger Fecher [États-Unis] ; Senad Divanovic [États-Unis] ; George S. Deepe [États-Unis] ; Kavitha Subramanian Vignesh [États-Unis]Source :
- Cell reports [ 2211-1247 ] ; 2019.
Abstract
Alternatively activated (M2) macrophages promote wound healing but weaken antimicrobial defenses. The mechanisms that enforce macrophage divergence and dictate the phenotypic and metabolic characteristics of M2 macrophages remain elusive. We show that alternative activation with interleukin (IL)-4 induces expression of metallothionein 3 (MT3) that regulates macrophage polarization and function. MT3 was requisite for metabolic reprograming in IL-4-stimulated macrophages or M(IL-4) macrophages to promote mitochondrial respiration and suppress glycolysis. MT3 fostered an M(IL-4) phenotype, suppressed hypoxia inducible factor (HIF)1α activation, and thwarted the emergence of a proinflammatory M1 program in macrophages. MT3 deficiency augmented macrophage plasticity, resulting in enhanced interferon γ (IFNγ) responsiveness and a dampened M(IL-4) phenotype. Thus, MT3 programs the phenotype and metabolic fate of M(IL-4) macrophages.
Url:
DOI: 10.1016/j.celrep.2019.05.093
PubMed: 31242420
PubMed Central: 6664296
Affiliations:
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<author><name sortKey="Divanovic, Senad" sort="Divanovic, Senad" uniqKey="Divanovic S" first="Senad" last="Divanovic">Senad Divanovic</name>
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<author><name sortKey="Vignesh, Kavitha Subramanian" sort="Vignesh, Kavitha Subramanian" uniqKey="Vignesh K" first="Kavitha Subramanian" last="Vignesh">Kavitha Subramanian Vignesh</name>
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<series><title level="j">Cell reports</title>
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<front><div type="abstract" xml:lang="en"><title>SUMMARY</title>
<p id="P3">Alternatively activated (M2) macrophages promote wound healing but weaken antimicrobial defenses. The mechanisms that enforce macrophage divergence and dictate the phenotypic and metabolic characteristics of M2 macrophages remain elusive. We show that alternative activation with interleukin (IL)-4 induces expression of metallothionein 3 (MT3) that regulates macrophage polarization and function. MT3 was requisite for metabolic reprograming in IL-4-stimulated macrophages or M(IL-4) macrophages to promote mitochondrial respiration and suppress glycolysis. MT3 fostered an M(IL-4) phenotype, suppressed hypoxia inducible factor (HIF)1α activation, and thwarted the emergence of a proinflammatory M1 program in macrophages. MT3 deficiency augmented macrophage plasticity, resulting in enhanced interferon γ (IFNγ) responsiveness and a dampened M(IL-4) phenotype. Thus, MT3 programs the phenotype and metabolic fate of M(IL-4) macrophages.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101573691</journal-id>
<journal-id journal-id-type="pubmed-jr-id">39703</journal-id>
<journal-id journal-id-type="nlm-ta">Cell Rep</journal-id>
<journal-id journal-id-type="iso-abbrev">Cell Rep</journal-id>
<journal-title-group><journal-title>Cell reports</journal-title>
</journal-title-group>
<issn pub-type="epub">2211-1247</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31242420</article-id>
<article-id pub-id-type="pmc">6664296</article-id>
<article-id pub-id-type="doi">10.1016/j.celrep.2019.05.093</article-id>
<article-id pub-id-type="manuscript">NIHMS1532877</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Metallothionein 3 Controls the Phenotype and Metabolic Programming of Alternatively Activated Macrophages</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Chowdhury</surname>
<given-names>Debabrata</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alrefai</surname>
<given-names>Hani</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Figueroa</surname>
<given-names>Julio A. Landero</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Candor</surname>
<given-names>Kathleen</given-names>
</name>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Porollo</surname>
<given-names>Aleksey</given-names>
</name>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Fecher</surname>
<given-names>Roger</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Divanovic</surname>
<given-names>Senad</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Deepe</surname>
<given-names>George S.</given-names>
<suffix>Jr.</suffix>
</name>
<xref ref-type="aff" rid="A1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vignesh</surname>
<given-names>Kavitha Subramanian</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A8">8</xref>
<xref rid="CR1" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA</aff>
<aff id="A2"><label>2</label>
University of Cincinnati/Agilent Technologies Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USA</aff>
<aff id="A3"><label>3</label>
Center for Autoimmune Genomics and Etiology and Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA</aff>
<aff id="A4"><label>4</label>
Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, New York, NY 10467, USA</aff>
<aff id="A5"><label>5</label>
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA</aff>
<aff id="A6"><label>6</label>
Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA</aff>
<aff id="A7"><label>7</label>
These authors contributed equally</aff>
<aff id="A8"><label>8</label>
Lead Contact</aff>
<author-notes><fn fn-type="con" id="FN1"><p id="P1">AUTHOR CONTRIBUTIONS</p>
<p id="P2">K.S.V. wrote the manuscript, performed experiments, and interpreted the data; D.C. performed <italic>in vitro</italic>
experiments with WT and <italic>Mt3</italic>
<sup>−/−</sup>
mice; H.A. performed ECAR and OCR analysis in WT and <italic>Mt3</italic>
<sup>−/−</sup>
mice <italic>in vitro</italic>
and <italic>in vivo</italic>
; J.A.L.F. and K.C. performed chromatographic separations and Zn isotope dilution analysis; R.F. contributed to western blot data from <italic>Lyz2CreHif</italic>
<sup><italic>fl/fl</italic>
</sup>
mice; S.D. provided guidance for metabolic studies; and A.P., J.A.L.F., G.S.D., and K.S.V. supervised the work.</p>
</fn>
<corresp id="CR1"><label>*</label>
Correspondence: <email>kavitha.subramanian@uc.edu</email>
</corresp>
<fn fn-type="COI-statement" id="FN3"><p id="P69">DECLARATION OF INTERESTS</p>
<p id="P70">The authors declare no competing interests.</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>24</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="ppub"><day>25</day>
<month>6</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>30</day>
<month>7</month>
<year>2019</year>
</pub-date>
<volume>27</volume>
<issue>13</issue>
<fpage>3873</fpage>
<lpage>3886.e7</lpage>
<pmc-comment>elocation-id from pubmed: 10.1016/j.celrep.2019.05.093</pmc-comment>
<abstract id="ABS1"><title>SUMMARY</title>
<p id="P3">Alternatively activated (M2) macrophages promote wound healing but weaken antimicrobial defenses. The mechanisms that enforce macrophage divergence and dictate the phenotypic and metabolic characteristics of M2 macrophages remain elusive. We show that alternative activation with interleukin (IL)-4 induces expression of metallothionein 3 (MT3) that regulates macrophage polarization and function. MT3 was requisite for metabolic reprograming in IL-4-stimulated macrophages or M(IL-4) macrophages to promote mitochondrial respiration and suppress glycolysis. MT3 fostered an M(IL-4) phenotype, suppressed hypoxia inducible factor (HIF)1α activation, and thwarted the emergence of a proinflammatory M1 program in macrophages. MT3 deficiency augmented macrophage plasticity, resulting in enhanced interferon γ (IFNγ) responsiveness and a dampened M(IL-4) phenotype. Thus, MT3 programs the phenotype and metabolic fate of M(IL-4) macrophages.</p>
</abstract>
<abstract id="ABS2" abstract-type="graphical"><title>Graphical Abstract</title>
<p id="P4"><graphic xlink:href="nihms-1532877-f0001.jpg" position="anchor" orientation="portrait"></graphic>
</p>
</abstract>
<abstract id="ABS3" abstract-type="summary"><title>In Brief</title>
<p id="P5">Metabolic reprograming in interleukin (IL)-4-stimulated macrophages (M(IL-4) macrophages) have a distinct polarization and metabolic phenotype. Chowdhury et al. show that metallothionein 3 (MT3) is required for M(IL-4) polarization and oxidative metabolism. MT3 suppresses glycolysis and the emergence of a proinflammatory M1 program. MT3 is a gatekeeper that subverts interferon (IFNγ) responses and intracellular defenses in M(IL-4) macrophages.</p>
</abstract>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>États-Unis</li>
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<name sortKey="Deepe, George S" sort="Deepe, George S" uniqKey="Deepe G" first="George S." last="Deepe">George S. Deepe</name>
<name sortKey="Divanovic, Senad" sort="Divanovic, Senad" uniqKey="Divanovic S" first="Senad" last="Divanovic">Senad Divanovic</name>
<name sortKey="Divanovic, Senad" sort="Divanovic, Senad" uniqKey="Divanovic S" first="Senad" last="Divanovic">Senad Divanovic</name>
<name sortKey="Fecher, Roger" sort="Fecher, Roger" uniqKey="Fecher R" first="Roger" last="Fecher">Roger Fecher</name>
<name sortKey="Figueroa, Julio A Landero" sort="Figueroa, Julio A Landero" uniqKey="Figueroa J" first="Julio A. Landero" last="Figueroa">Julio A. Landero Figueroa</name>
<name sortKey="Porollo, Aleksey" sort="Porollo, Aleksey" uniqKey="Porollo A" first="Aleksey" last="Porollo">Aleksey Porollo</name>
<name sortKey="Vignesh, Kavitha Subramanian" sort="Vignesh, Kavitha Subramanian" uniqKey="Vignesh K" first="Kavitha Subramanian" last="Vignesh">Kavitha Subramanian Vignesh</name>
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