A novel function for 15-lipoxygenases in cholesterol homeostasis and CCL17 production in human macrophages

  • Arachidonate 15-lipoxygenase (ALOX15) and arachidonate 15-lipoxygenase, type B (ALOX15B) catalyze the dioxygenation of polyunsaturated fatty acids and are upregulated in human alternatively activated macrophages (AAMs) induced by Th2 cytokine interleukin-4 (IL-4) and/or interleukin-13. Known primarily for roles in bioactive lipid mediator synthesis, 15-lipoxygenases (15-LOXs) have been implicated in various macrophage functions including efferocytosis and ferroptosis. Using a combination of inhibitors and siRNAs to suppress 15-LOX isoforms, we studied the role of 15-LOXs in cellular cholesterol homeostasis and immune function in naïve and AAMs. Silencing or inhibiting the 15-LOX isoforms impaired sterol regulatory element binding protein (SREBP)-2 signaling by inhibiting SREBP-2 processing into mature transcription factor and reduced SREBP-2 binding to sterol regulatory elements and subsequent target gene expression. Silencing ALOX15B reduced cellular cholesterol and the cholesterol intermediates desmosterol, lanosterol, 24,25-dihydrolanosterol, and lathosterol as well as oxysterols in IL-4-stimulated macrophages. In addition, attenuating both 15-LOX isoforms did not generally affect IL-4 gene expression but rather uniquely impacted IL-4-induced CCL17 production in an SREBP-2-dependent manner resulting in reduced T cell migration to macrophage conditioned media. In conclusion, we identified a novel role for ALOX15B, and to a lesser extent ALOX15, in cholesterol homeostasis and CCL17 production in human macrophages.

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Author:Ryan G. Snodgrass, Ekaterina Zezina, Dmitry Namgaladze, Sahil Gupta, Carlo Federico Angioni, Gerd GeisslingerORCiDGND, Dieter Lütjohann, Bernhard BrüneORCiD
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30197642
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Kottarappat N. Dileepan
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/08/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/09/20
Tag:arachidonate 15-lipoxygenase; chemokine; cholesterol; interleukin-4; lipoxygenase; macrophage; sterol regulatory element binding protein-2; type B
Issue:Art. 1906
Page Number:16
First Page:1
Last Page:16
Copyright: © 2018 Snodgrass, Zezina, Namgaladze, Gupta, Angioni, Geisslinger, Lütjohann 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