Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production.
Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production.
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DOI：
10.1038/s42255-023-00934-4
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发表时间：
2023-11
影响因子：
20.8
通讯作者：
Andrew D Hildreth;Eddie T Padilla;Meha Gupta;Y. Wong;Ryan Sun;Akshara R Legala;Timothy E. O’Sullivan
中科院分区：
文献类型：
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作者：
Andrew D Hildreth;Eddie T Padilla;Meha Gupta;Y. Wong;Ryan Sun;Akshara R Legala;Timothy E. O’Sullivan
肥胖与慢性低级别白色脂肪组织(WAT)炎症有关，这种炎症可能导致哺乳动物的胰岛素抵抗。以前的研究已经证实，白介素12是肥胖症期间WAT炎症和代谢功能障碍的关键上游调节因子。然而，启动Wat IL-12产生的细胞类型和机制仍不清楚。在这里，我们通过分析小鼠和人的Wat单细胞转录数据集、IL-12报告鼠和IL-12p70蛋白水平的酶联免疫吸附试验，证明了传统的1型树突状细胞(CDC1s)是肥胖过程中Wat IL-12的细胞来源。我们证明，CDC1s通过增加第1组固有淋巴细胞干扰素-γ的产生和炎性巨噬细胞的聚集而促进肥胖相关的炎症。在饮食诱导的肥胖期间，cDC1s的可诱导耗竭增加了Wat胰岛素敏感性和全身糖耐量。从机制上讲，Wat cDC1s对含有自身DNA的凋亡体的内吞作用驱动干扰素基因刺激物(STINE)依赖的IL-12的产生。综上所述，这些结果表明，Wat cDC1s在肥胖过程中是脂肪组织炎症和代谢功能障碍的关键调节因子。
Obesity is associated with chronic low-grade white adipose tissue (WAT) inflammation that can contribute to the development of insulin resistance in mammals. Previous studies have identified interleukin (IL)-12 as a critical upstream regulator of WAT inflammation and metabolic dysfunction during obesity. However, the cell types and mechanisms that initiate WAT IL-12 production remain unclear. Here we show that conventional type 1 dendritic cells (cDC1s) are the cellular source of WAT IL-12 during obesity through analysis of mouse and human WAT single-cell transcriptomic datasets, IL-12 reporter mice and IL-12p70 protein levels by enzyme-linked immunosorbent assay. We demonstrate that cDC1s contribute to obesity-associated inflammation by increasing group 1 innate lymphocyte interferon-γ production and inflammatory macrophage accumulation. Inducible depletion of cDC1s increased WAT insulin sensitivity and systemic glucose tolerance during diet-induced obesity. Mechanistically, endocytosis of apoptotic bodies containing self-DNA by WAT cDC1s drives stimulator of interferon genes (STING)-dependent IL-12 production. Together, these results suggest that WAT cDC1s act as critical regulators of adipose tissue inflammation and metabolic dysfunction during obesity.