Profiling the role of conventional type 1 dendritic cells during obesity-associated inflammation

项目摘要 肥胖已成为一种全球性的健康流行病，影响着世界近30%的人口。肥胖是 与慢性低度炎症的发展有关，慢性炎症可导致胰岛素抵抗， 肥胖相关炎症在诱导II型糖尿病（T2 DM）中的作用。但 肥胖期间脂肪组织炎症的根本原因仍然知之甚少。积累和 已经显示组织驻留巨噬细胞的激活有助于炎症和胰岛素抵抗 在小鼠中，由1型免疫细胞如CD 8+和CD 4 + TH 1细胞，自然杀伤（NK）细胞， 和1型先天淋巴样细胞（ILC 1）。我们的实验室以前已经表明，ILC 1衍生的干扰素γ（IFN-γ） γ）驱动促炎性巨噬细胞积聚，并导致肥胖相关的胰岛素抵抗， 白细胞介素-12（IL-12）。以前的研究结果表明，IL-12信号在肥胖相关的 炎症和随后的代谢功能障碍，但肥胖期间IL-12的细胞来源仍然存在 未知常规的1型树突状细胞（cDC 1）是1型免疫应答的有效激活剂， 产生IL-12以响应病原体攻击。然而，cDC 1是否在脂肪内产生IL-12， 肥胖期间的组织是未知的。此外，虽然肥胖相关的树突状细胞浸润增加， 尽管已经报道过，但对树突状细胞募集到WAT中的机制知之甚少。 因此，cDC 1在增强脂肪组织炎症和胰岛素抵抗中的精确功能在 肥胖仍有待阐明。 我的初步数据支持cDC 1被NK细胞募集到脂肪组织的中心假设- 衍生的XCL 1，因此它们通过IL-12产生启动促炎细胞因子应答，以促进 肥胖相关的炎症和胰岛素抵抗。我的理论基础是cDC 1在两个人体内积累， 和小鼠脂肪组织，并且它们是肥胖小鼠模型中IL-12的主要产生者。 饮食引起的肥胖此外，我们发现XCL 1-XCR 1信号轴在肥胖患者中富集， 小鼠NK细胞的基因耗竭显著降低了脂肪组织中cDC 1的积累。我 我建议使用以下目标来测试我的中心假设：目标1：确定cDC 1在饮食中的作用- 诱导肥胖（DIO）和目标2：阐明驱动cDC 1积累到脂肪中的机制 DIO期间的组织。这种方法是重要的，因为完成拟议的研究将提供新的 深入了解先天免疫系统如何促进肥胖相关免疫系统的启动和增强。 炎症和胰岛素抵抗，为开发新的治疗靶点打开了大门， 预防胰岛素抵抗的发展和T2 DM的发作。

PROJECT SUMMARY Obesity has become a global health epidemic, affecting nearly 30% of the world’s population. Obesity is associated with the development chronic low-grade inflammation which can lead to insulin resistance, implicating a role for obesity-associated inflammation in the induction of type II diabetes mellitus (T2DM). However, the underlying causes of adipose tissue inflammation during obesity remain poorly understood. Accumulation and activation of tissue-resident macrophages has been shown to contribute to inflammation and insulin resistance in mice, a process regulated by type 1 immune cell such as CD8+ and CD4+ TH1 cells, natural killer (NK) cells, and type 1 innate lymphoid cells (ILC1). Our lab has shown previously that ILC1-derived interferon gamma (IFN- γ) drives proinflammatory macrophage accumulation and contributes to obesity-associated insulin resistance in response to interleukin-12 (IL-12). Previous findings have implicated IL-12 signaling in obesity-associated inflammation and subsequent metabolic dysfunction, but the cellular sources of IL-12 during obesity remain unknown. Conventional type 1 dendritic cells (cDC1) are potent activators of type 1 immune responses and produce IL-12 in response to pathogen challenge. However, whether cDC1 produce IL-12 within the adipose tissue during obesity is unknown. Furthermore, while obesity-associated increases in dendritic cell infiltration have been reported, the mechanisms that govern dendritic cell recruitment into the WAT are poorly understood. As such, the precise function of cDC1 in potentiating adipose tissue inflammation and insulin resistance during obesity remains to be elucidated. My preliminary data supports the central hypothesis that cDC1 are recruited into the adipose tissue by NK cell- derived XCL1, whereupon they initiate proinflammatory cytokine responses via IL-12 production to contribute to obesity-associated inflammation and insulin resistance. My rationale is that cDC1 accumulate in both human and mouse adipose tissue during obesity and that they are the major producers of IL-12 in mouse models of diet-induced obesity. Furthermore, we find that the XCL1-XCR1 signaling axis is enriched in obese patients and that genetic depletion of NK cells in mice significantly reduces cDC1 accumulation within the adipose tissue. I propose to test my central hypothesis using the following aims: Aim 1: determine the role of cDC1 during diet- induced obesity (DIO) and Aim 2: elucidate the mechanisms that drive cDC1 accumulation into the adipose tissue during DIO. This approach is significant, as completion of the proposed research will provide novel insights into how the innate immune system contributes to the initiation and potentiation of obesity-associated inflammation and insulin resistance, opening the door for the development of novel therapeutic targets aimed at preventing the development of insulin resistance and onset of T2DM.