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Efferocytosis potentiates the expression of arachidonate 15-lipoxygenase (ALOX15) in alternatively activated human macrophages through LXR activation
Cell Death and Differentiation ( IF 12.4 ) Pub Date : 2020-11-11 , DOI: 10.1038/s41418-020-00652-4
Ryan G Snodgrass 1 , Yvonne Benatzy 1 , Tobias Schmid 1 , Dmitry Namgaladze 1 , Malwina Mainka 2 , Nils Helge Schebb 2 , Dieter Lütjohann 3 , Bernhard Brüne 1
Affiliation  

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.



中文翻译:

Efferocytosis 通过 LXR 激活增强了交替激活的人巨噬细胞中花生四烯酸 15-脂氧合酶 (ALOX15) 的表达

巨噬细胞获得抗炎和促消退功能,以促进炎症消退和促进组织修复。虽然交替活化的巨噬细胞 (AAM),也称为 M2 巨噬细胞,但被 2 型 (Th2) 细胞因子 IL-4 或 IL-13 极化有助于抑制炎症反应,并在伤口愈合中发挥关键作用,同时暴露于凋亡细胞(ACs)增强抗炎和组织修复基因的表达。鉴于协调甾醇代谢和免疫细胞功能的肝 X 受体 (LXRs) 在清除 ACs 中起重要作用,我们研究了吞噬 ACs 后 LXR 激活是否选择性地增强 Th2 细胞因子依赖性基因在原代人类中的表达AAM。我们显示 AC 摄取同时上调 LXR 依赖性,但抑制巨噬细胞中 SREBP-2 依赖性基因表达,这两者都可以通过抑制 Niemann-Pick C1 (NPC1) 介导的溶酶体甾醇转运来防止。同时,巨噬细胞积累甾醇生物合成中间体去甾醇、羊毛甾醇、羊毛甾醇和二氢羊毛甾醇,但不积累胆固醇衍生的氧甾醇。使用全局转录组分析,我们确定了抗炎和促分解基因,包括白细胞介素 1 受体拮抗剂 (IL1RN) 和花生四烯酸 15-脂氧合酶 (ALOX15),其在同时暴露于 ACs 或 LXR 激动剂 T0901317 (T09) 和Th2细胞因子。我们显示,通过 LXR 激活引发巨噬细胞增强了细胞合成抑制炎症的专门的分解前介质 (SPM) 前体 15-HETE 和 17-HDHA 以及 resolvin D5 的能力。沉默巨噬细胞中的 LXRα 和 LXRβ 通过同时刺激 AC 或 T09 和 IL-13 减弱 ALOX15 表达的增强。总的来说,我们确定了一种以前未被识别的调节机制,即 LXR 整合 AC 摄取以选择性地塑造 AAM 中的 Th2 依赖性基因表达。

更新日期:2020-11-12
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