TY  - JOUR
A1  - Snodgrass, Ryan G.
A1  - Zezina, Ekaterina
A1  - Namgaladze, Dmitry
A1  - Gupta, Sahil
A1  - Angioni, Carlo Federico
A1  - Geisslinger, Gerd
A1  - Lütjohann, Dieter
A1  - Brüne, Bernhard
T1  - A novel function for 15-lipoxygenases in cholesterol homeostasis and CCL17 production in human macrophages
T2  - Frontiers in immunology
N2  - 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.
KW  - macrophage
KW  - arachidonate 15-lipoxygenase
KW  - type B
KW  - lipoxygenase
KW  - chemokine
KW  - cholesterol
KW  - interleukin-4
KW  - sterol regulatory element binding protein-2
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46638
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-466386
SN  - 1664-3224
N1  - 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.
VL  - 9
IS  - Art. 1906
SP  - 1
EP  - 16
PB  - Frontiers Media
CY  - Lausanne
ER  -