Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation

  • Macrophages acquire anti-inflammatory and proresolving functions to facilitate resolution of inflammation and promote tissue repair. While alternatively activated macrophages (AAMs), also referred to as M2 macrophages, polarized by type 2 (Th2) cytokines IL-4 or IL-13 contribute to the suppression of inflammatory responses and play a pivotal role in wound healing, contemporaneous exposure to apoptotic cells (ACs) potentiates the expression of anti-inflammatory and tissue repair genes. Given that liver X receptors (LXRs), which coordinate sterol metabolism and immune cell function, play an essential role in the clearance of ACs, we investigated whether LXR activation following engulfment of ACs selectively potentiates the expression of Th2 cytokine-dependent genes in primary human AAMs. We show that AC uptake simultaneously upregulates LXR-dependent, but suppresses SREBP-2-dependent gene expression in macrophages, which are both prevented by inhibiting Niemann–Pick C1 (NPC1)-mediated sterol transport from lysosomes. Concurrently, macrophages accumulate sterol biosynthetic intermediates desmosterol, lathosterol, lanosterol, and dihydrolanosterol but not cholesterol-derived oxysterols. Using global transcriptome analysis, we identify anti-inflammatory and proresolving genes including interleukin-1 receptor antagonist (IL1RN) and arachidonate 15-lipoxygenase (ALOX15) whose expression are selectively potentiated in macrophages upon concomitant exposure to ACs or LXR agonist T0901317 (T09) and Th2 cytokines. We show priming macrophages via LXR activation enhances the cellular capacity to synthesize inflammation-suppressing specialized proresolving mediator (SPM) precursors 15-HETE and 17-HDHA as well as resolvin D5. Silencing LXRα and LXRβ in macrophages attenuates the potentiation of ALOX15 expression by concomitant stimulation of ACs or T09 and IL-13. Collectively, we identify a previously unrecognized mechanism of regulation whereby LXR integrates AC uptake to selectively shape Th2-dependent gene expression in AAMs.
Metadaten
Author:Ryan G. SnodgrassORCiD, Yvonne BenatzyORCiD, Tobias SchmidORCiDGND, Dmitry NamgaladzeORCiD, Malwina Mainka, Nils Helge SchebbORCiDGND, Dieter LütjohannORCiD, Bernhard BrüneORCiD
URN:urn:nbn:de:hebis:30:3-813232
DOI:https://doi.org/10.1038/s41418-020-00652-4
ISSN:1476-5403
Parent Title (English):Cell death and differentiation
Publisher:Nature Publishing Group ; Macmillan
Place of publication:Houndmills, Basingstoke ; London
Document Type:Article
Language:English
Date of Publication (online):2020/11/11
Date of first Publication:2020/11/11
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/01/31
Tag:Cell death and immune response; Chronic inflammation; Sterols
Volume:28
Issue:4
Page Number:16
First Page:1301
Last Page:1316
Note:
This study was supported by Deutsche Forschungsgemeinschaft SFB1039 TP A05, B04, RTG 2336/1 TP06. Open Access funding enabled and organized by Projekt DEAL.
HeBIS-PPN:517873753
Institutes:Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International