TY  - JOUR
A1  - Namgaladze, Dmitry
A1  - Zukunft, Sven
A1  - Schnütgen, Frank
A1  - Kurrle, Nina Susanne
A1  - Fleming, Ingrid
A1  - Fuhrmann, Dominik Christian
A1  - Brüne, Bernhard
T1  - Polarization of human macrophages by interleukin-4 does not require ATP-citrate lyase
T2  - Frontiers in immunology
N2  - 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.
KW  - macrophage
KW  - ATP-citrate lyase
KW  - acetyl-CoA
KW  - interleukin-4
KW  - histone acetylation
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/49283
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-492833
SN  - 1664-3224
N1  - 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.
VL  - 9
IS  - Art. 2858
SP  - 1
EP  - 11
PB  - Frontiers Media
CY  - Lausanne
ER  -