Loss of stearoyl-CoA desaturase 2 disrupts inflammatory response in macrophages.
Loss of stearoyl-CoA desaturase 2 disrupts inflammatory response in macrophages.
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DOI：
10.1128/mbio.00925-23
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发表时间：
2023-08-31
期刊：
影响因子：
6.4
通讯作者：
Apte, Rajendra S.
中科院分区：
文献类型：
--
作者：
Lin, Joseph B.;Mora, Amy;Wang, Tzu Jui;Santeford, Andrea;Usmani, Darksha;Ligon, Marianne M.;Mysorekar, Indira U.;Apte, Rajendra S.
巨噬细胞是巡逻组织的先天免疫细胞，是检测感染的第一反应者。它们协调宿主免疫反应，消除入侵的病原体以及随后从炎症到组织修复的转变。巨噬细胞功能障碍会导致与年龄相关的病理，包括高龄时的低度炎症，称为“炎症”。我们的实验室之前发现，巨噬细胞中脂肪酸去饱和酶硬脂酰辅酶A去饱和酶 2 (SCD2) 的表达会随着年龄的增长而下降。在此，我们描述了 SCD2 缺陷对小鼠巨噬细胞的精确细胞影响。我们发现从巨噬细胞中删除 Scd2 会失调基础脂多糖 (LPS) 刺激的许多炎症相关基因的转录。具体来说，从巨噬细胞中删除 Scd2 会减少 IL1b 转录物的基础表达和 LPS 诱导的表达，这与前体 IL1B 蛋白的产生和成熟 IL1B 的释放减少相对应。此外，我们还发现 SCD2 缺陷型巨噬细胞中自噬的破坏和不饱和心磷脂的消耗。为了评估 SCD2 在巨噬细胞对感染的反应中的功能相关性，我们用尿路致病性大肠杆菌攻击缺乏 SCD2 的巨噬细胞，发现细胞内细菌的清除受损。细胞内细菌负担的增加伴随着促炎细胞因子 IL6 和 TNF 释放的增加，但 IL1B 的释放减少。综上所述，这些结果表明 Scd2 的巨噬细胞表达对于维持巨噬细胞对炎症刺激的反应是必需的。脂肪酸代谢和基本巨噬细胞效应器功能之间的这种联系可能与多种与年龄相关的病理有关。巨噬细胞是对感染做出反应的免疫细胞，但它们的功能障碍与许多与年龄相关的疾病有关。最近的证据表明，在衰老的生物体中，巨噬细胞中脂肪酸酶（硬脂酰辅酶 A 去饱和酶 2）的表达会下降。在这项工作中，我们描述了巨噬细胞中硬脂酰辅酶 A 去饱和酶 2 缺乏时的影响。我们确定了当关键脂肪酸酶的表达减少时，巨噬细胞对感染的炎症反应可能会受到影响，这些发现可能为巨噬细胞如何导致与年龄相关的疾病提供细胞洞察。
Macrophages are innate immune cells that patrol tissues and are the first responders to detect infection. They orchestrate the host immune response in eliminating invading pathogens and the subsequent transition from inflammation to tissue repair. Macrophage dysfunction contributes to age-related pathologies, including low-grade inflammation in advanced age that is termed “inflammaging.” Our laboratory has previously identified that macrophage expression of a fatty acid desaturase, stearoyl-CoA desaturase 2 (SCD2), declines with age. Herein, we delineate the precise cellular effects of SCD2 deficiency in murine macrophages. We found that deletion of Scd2 from macrophages dysregulated basal and bacterial lipopolysaccharide (LPS)-stimulated transcription of numerous inflammation-associated genes. Specifically, deletion of Scd2 from macrophages decreased basal and LPS-induced expression of Il1b transcript that corresponded to decreased production of precursor IL1B protein and release of mature IL1B. Furthermore, we identified disruptions in autophagy and depletion of unsaturated cardiolipins in SCD2-deficient macrophages. To assess the functional relevance of SCD2 in the macrophage response to infection, we challenged SCD2-deficient macrophages with uropathogenic Escherichia coli and found that there was impaired clearance of intracellular bacteria. This increased burden of intracellular bacteria was accompanied by increased release of pro-inflammatory cytokines IL6 and TNF but decreased IL1B. Taken together, these results indicate that macrophage expression of Scd2 is necessary for maintaining the macrophage response to inflammatory stimuli. This link between fatty acid metabolism and fundamental macrophage effector functions may potentially be relevant to diverse age-related pathologies. Macrophages are immune cells that respond to infection, but their dysfunction is implicated in many age-related diseases. Recent evidence showed that macrophage expression of a fatty acid enzyme, stearoyl-CoA desaturase 2, declines in aged organisms. In this work, we characterize the effects when stearoyl-CoA desaturase 2 is deficient in macrophages. We identify aspects of the macrophage inflammatory response to infection that may be affected when expression of a key fatty acid enzyme is decreased, and these findings may provide cellular insight into how macrophages contribute to age-related diseases.
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