Polarization of human macrophages by interleukin-4 does not require ATP-citrate lyase

  • Macrophages exposed to the Th2 cytokines interleukin (IL) IL-4 and IL-13 exhibit a distinct transcriptional response, commonly referred to as M2 polarization. Recently, IL-4-induced polarization of murine bone marrow-derived macrophages (BMDMs) has been linked to acetyl-CoA levels through the activity of the cytosolic acetyl-CoA-generating enzyme ATP-citrate lyase (ACLY). Here, we studied how ACLY regulated IL-4-stimulated gene expression in human monocyte-derived macrophages (MDMs). Although multiple ACLY inhibitors attenuated IL-4-induced target gene expression, this effect could not be recapitulated by silencing ACLY expression. Furthermore, ACLY inhibition failed to alter cellular acetyl-CoA levels and histone acetylation. We generated ACLY knockout human THP-1 macrophages using CRISPR/Cas9 technology. While these cells exhibited reduced histone acetylation levels, IL-4-induced gene expression remained intact. Strikingly, ACLY inhibitors still suppressed induction of target genes by IL-4 in ACLY knockout cells, suggesting off-target effects of these drugs. Our findings suggest that ACLY may not be the major regulator of nucleocytoplasmic acetyl-CoA and IL-4-induced polarization in human macrophages. Furthermore, caution should be warranted in interpreting the impact of pharmacological inhibition of ACLY on gene expression.

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Author:Dmitry Namgaladze, Sven Zukunft, Frank SchnütgenORCiDGND, Nina Susanne KurrleORCiDGND, Ingrid FlemingORCiD, Dominik Christian FuhrmannORCiDGND, Bernhard BrüneORCiD
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30568658
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Alexandre Corthay
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/12/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/03/05
Tag:ATP-citrate lyase; acetyl-CoA; histone acetylation; interleukin-4; macrophage
Issue:Art. 2858
Page Number:11
First Page:1
Last Page:11
Copyright © 2018 Namgaladze, Zukunft, Schnütgen, Kurrle, Fleming, Fuhrmann and Brüne. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Institutes:Medizin / Medizin
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0