Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner
Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner
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DOI：
10.1016/j.cell.2019.05.054
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发表时间：
2019-07-25
期刊：
影响因子：
64.5
通讯作者：
Amit, Ido
中科院分区：
文献类型：
--
作者：
Jaitin, Diego Adhemar;Adlung, Lorenz;Amit, Ido
存在于白色脂肪组织中的免疫细胞已被强调为促成代谢性疾病的发病机制的重要因素，但在肥胖期间驱动脂肪组织免疫细胞重塑的分子调节剂在很大程度上仍然未知。使用索引和转录单细胞分选，我们全面映射所有脂肪组织免疫群体在小鼠和人类肥胖。我们描述了一个新的和保守的Trem2（+）脂质相关巨噬细胞（LAM）子集，并确定标记，空间定位，起源和功能途径与这些细胞。小鼠中Trem2的基因消融全面抑制下游分子LAM程序，导致脂肪细胞肥大以及全身性高胆固醇血症、体脂积累和葡萄糖耐受不良。这些发现将Trem2信号传导确定为巨噬细胞响应组织水平脂质稳态丧失的主要途径，突出了Trem2作为多种组织中代谢病理学的关键传感器和代谢疾病的潜在治疗靶点。
Immune cells residing in white adipose tissue have been highlighted as important factors contributing to the pathogenesis of metabolic diseases, but the molecular regulators that drive adipose tissue immune cell remodeling during obesity remain largely unknown. Using index and transcriptional single-cell sorting, we comprehensively map all adipose tissue immune populations in both mice and humans during obesity. We describe a novel and conserved Trem2(+) lipid-associated macrophage (LAM) subset and identify markers, spatial localization, origin, and functional pathways associated with these cells. Genetic ablation of Trem2 in mice globally inhibits the downstream molecular LAM program, leading to adipocyte hypertrophy as well as systemic hyper-cholesterolemia, body fat accumulation, and glucose intolerance. These findings identify Trem2 signaling as a major pathway by which macrophages respond to loss of tissue-level lipid homeostasis, highlighting Trem2 as a key sensor of metabolic pathologies across multiple tissues and a potential therapeutic target in metabolic diseases.