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

点击翻译按钮获取中文摘要

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.