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

分析传统 1 型树突状细胞在肥胖相关炎症中的作用

基本信息

批准号：
10463474
负责人：
Andrew Douglas Hildreth
金额：
$ 4.68万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10463474
关键词：
Adipose tissue Adoptive Cell Transfers Adoptive Transfer Adult Affect Biological Assay Biological Models CD8B1 gene Cells Chemosensitization Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Data Dendritic Cells Development Economics Epidemic Feedback Gene Deletion Genetic Glucose Intolerance High Fat Diet Human Immune Immune response Infiltration Inflammation Innate Immune System Insulin Insulin Resistance Interferon Type II Interleukin-12 Lead Link Lymphoid Cell Mediating Metabolic Metabolic dysfunction Metabolic syndrome Monitor Mus Natural Killer Cells Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Population Process Production Reporter Reporting Research Risk Role Serum Signal Transduction Source Testing Th1 Cells Thinness Tissues Transcript United States Weight Gain XCL1 gene XCR1 gene cell type comorbidity cytokine diet-induced obesity global health insight macrophage mouse model new therapeutic target novel obese patients obese person pathogen prevent recruit response tumor microenvironment

项目摘要

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.

项目概要肥胖已成为全球健康流行病，影响着世界近30%的人口。与慢性低度炎症的发展相关，可导致胰岛素抵抗，这意味着肥胖相关炎症在诱导 II 型糖尿病 (T2DM) 中的作用。肥胖期间脂肪组织炎症的根本原因仍知之甚少。组织驻留巨噬细胞的激活已被证明会导致炎症和胰岛素抵抗在小鼠中，这一过程受 1 型免疫细胞（例如 CD8+ 和 CD4+ TH1 细胞、自然杀伤 (NK) 细胞、和 1 型先天淋巴细胞 (ILC1) 之前，我们的实验室已证明 ILC1 衍生的干扰素 γ (IFN-)。 γ) 驱动促炎性巨噬细胞积累并导致肥胖相关的胰岛素抵抗先前的研究结果表明 IL-12 信号传导与肥胖相关。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传统的 1 型树突状细胞 (cDC1) 是 1 型免疫反应的有效激活剂。产生IL-12以应对病原体攻击然而，cDC1是否在脂肪内产生IL-12。此外，肥胖期间树突状细胞浸润的增加尚不清楚。据报道，控制树突状细胞招募到 WAT 的机制尚不清楚。因此，cDC1 在增强脂肪组织炎症和胰岛素抵抗方面的精确功能肥胖仍有待阐明。我的初步数据支持中心假设，即 cDC1 被 NK 细胞招募到脂肪组织中 - 衍生的 XCL1，随后它们通过产生 IL-12 启动促炎细胞因子反应，从而促进我的理由是，cDC1 在人类体内积累。和肥胖期间的小鼠脂肪组织，并且它们是肥胖小鼠模型中 IL-12 的主要产生者此外，我们发现 XCL1-XCR1 信号轴在肥胖患者中丰富。小鼠体内 NK 细胞的基因缺失显着减少了脂肪组织内 cDC1 的积累。建议使用以下目标来检验我的中心假设：目标 1：确定 cDC1 在饮食过程中的作用诱导性肥胖 (DIO) 和目标 2：阐明驱动 cDC1 积累到脂肪中的机制这种方法意义重大，因为完成拟议的研究将提供新颖的方法。深入了解先天免疫系统如何促进肥胖相关疾病的发生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 T2DM 的发生。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production.

无菌性肝损伤通过 cDC1 内在的 cGAS-STING 依赖性 IL-12 产生诱导保护性组织驻留 cDC1-ILC1 回路。

DOI：
发表时间：
2023-02-28
期刊：
影响因子：
8.8
作者：
Hildreth, Andrew D;Padilla, Eddie T;Tafti, Rana Yakhshi;Legala, Akshara R;O'Sullivan, Timothy E
通讯作者：
O'Sullivan, Timothy E

Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production.

脂肪 cDC1 通过 STING 依赖性 IL-12 产生导致肥胖相关炎症。

DOI：
10.1038/s42255-023-00934-4
发表时间：
2023-11-23
期刊：
Nature metabolism
影响因子：
20.8
作者：
Andrew D Hildreth;Eddie T Padilla;Meha Gupta;Y. Wong;Ryan Sun;Akshara R Legala;Timothy E. O’Sullivan
通讯作者：
Timothy E. O’Sullivan