Abstract
Chronic inflammation is evident in the adipose tissue and periphery of patients with obesity, as well as mouse models of obesity. T cell subsets in obese adipose tissue are skewed towards Th1- and Th17-associated phenotypes and their secreted cytokines contribute to obesity-associated inflammation. Our lab recently identified a novel, myeloid-derived CD45+DDR2+ cell subset that modulates T cell activity. The current study sought to determine how these myeloid-derived CD45+DDR2+ cells are altered in the adipose tissue and peripheral blood of preobese mice and how this population modulates T cell activity. C57BL/6 mice were fed with a diet high in milkfat (60%·kcal, HFD) ad libitum until a 20% increase in total body weight was reached, and myeloid-derived CD45+DDR2+ cells and CD4+ T cells in visceral adipose tissue (VAT), mammary gland-associated adipose tissue (MGAT), and peripheral blood (PB) were phenotypically analyzed. Also analyzed was whether mediators from MGAT-primed myeloid-derived CD45+DDR2+ cells stimulate normal CD4+ T cell cytokine production. A higher percentage of myeloid-derived CD45+DDR2+ cells expressed the activation markers MHC II and CD80 in both VAT and MGAT of preobese mice. CD4+ T cells were preferentially skewed towards Th1- and Th17-associated phenotypes in the adipose tissue and periphery of preobese mice. In vitro, MGAT from HFD-fed mice triggered myeloid-derived CD45+DDR2+ cells to induce CD4+ T cell IFN-γ and TNF-α production. Taken together, this study shows that myeloid-derived CD45+DDR2+ cells express markers of immune activation and suggests that they play an immune modulatory role in the adipose tissue of preobese mice.
Highlights
Obesity is a complex disease that contributes to the development of type 2 diabetes (T2D), cardiovascular disease, and various cancers [1,2,3,4,5,6]
We have previously shown that hematopoietic stem cell- (HSC-)derived DDR2+ cells home to tumor via the Chemokine receptor 2 (CCR2)/monocyte-derived chemoattractant protein- (MCP-)1 axis and are capable of differentiating into fibroblasts in the local tumor environment [48]
One previous study showed that DDR2 is expressed on a subset of dendritic cells and that binding of collagen I to DDR2 leads to increased expression of the activation marker CD86 and increased production of IL-12, a proinflammatory cytokine involved in Th1-type skewing [47]
Summary
Obesity is a complex disease that contributes to the development of type 2 diabetes (T2D), cardiovascular disease, and various cancers [1,2,3,4,5,6]. Mouse models of high-fat diet- (HFD-) induced obesity are typically characterized by at least a 30% increase in total body weight and closely mimic human disease [7,8,9]. C57BL/6 mice fed with a HFD ad libitum for 16-20 weeks exhibit adipocyte hyperplasia, increased fat mass, hypertension, and impaired glucose sensitivity leading to T2D [7, 10, 11]. Less is known about the molecular and immune changes that occur before obesity is fully established. The current study is focused on the inflammatory changes that occur in the adipose tissue of HFD-fed preobese mice, which are characterized by a 20% increase in total body weight and more closely represent an overweight, or preobese condition vs obese condition [14]
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