HIF1α activation in dendritic cells under sterile conditions promotes an anti-inflammatory phenotype through accumulation of intracellular lipids.

Obesity is among the leading causes of elevated cardiovascular disease mortality and morbidity. Adipose tissue dysfunction, insulin resistance and inflammation are recognized as important risk factors for the development of cardiovascular disorders in obesity. Hypoxia appears to be a key factor in adipose tissue dysfunction affecting not only adipocytes but also immune cell function. Here we examined the effect of hypoxia-induced transcription factor HIF1α activation on classical dendritic cell (cDCs) function during obesity. We found that deletion of Hif1α on cDCs results in enhanced adipose-tissue inflammation and atherosclerotic plaque formation in a mouse model of obesity. This effect is mediated by HIF1α-mediated increased lipid synthesis, accumulation of lipid droplets and alter synthesis of lipid mediators. Our findings demonstrate that HIF1α activation in cDCs is necessary to control vessel wall inflammation.

Constitutive Activation of ß-Catenin in Conventional Dendritic Cells Increases the Insulin Reserve to Ameliorate the Development of Type 2 Diabetes in Mice.

ß-Cell failure is central to the development of type 2 diabetes mellitus (T2DM). Dysregulation of metabolic and inflammatory processes during obesity contributes to the loss of islet function and impaired ß-cell insulin secretion. Modulating the immune system, therefore, has the potential to ameliorate diseases. We report that inducing sustained expression of ß-catenin in conventional dendritic cells (cDCs) provides a novel mechanism to enhance ß-cell insulin secretion. Intriguingly, cDCs with constitutively activated ß-catenin induced islet expansion by increasing ß-cell proliferation in a model of diet-induced obesity. We further found that inflammation in these islets was reduced. Combined, these effects improved ß-cell insulin secretion, suggesting a unique compensatory mechanism driven by cDCs to generate a greater insulin reserve in response to obesity-induced insulin resistance. Our findings highlight the potential of immune modulation to improve ß-cell mass and function in T2DM.

Adipose tissue dendritic cells in steady-state.

Healthy white adipose tissue (WAT) participates in regulating systemic metabolism, whereas dysfunctional WAT plays a prominent role in the development of obesity-associated co-morbidities. Tissue-resident immune cells are important for maintaining WAT homeostasis, including conventional dendritic cells (cDCs) which are critical in the initiation and regulation of adaptive immune responses. Due to phenotypic overlap with other myeloid cells, the distinct contribution of WAT cDCs has been poorly understood. This review will discuss the contribution of cDCs in the maintenance of WAT homeostasis. In particular, the review will focus on the metabolic cross-talk between cDCs and adipocytes that regulates local immune responses during physiological conditions.

Visceral Adipose Tissue Immune Homeostasis Is Regulated by the Crosstalk between Adipocytes and Dendritic Cell Subsets.

Visceral adipose tissue (VAT) has multiple roles in orchestrating whole-body energy homeostasis. In addition, VAT is now considered an immune site harboring an array of innate and adaptive immune cells with a direct role in immune surveillance and host defense. We report that conventional dendritic cells (cDCs) in VAT acquire a tolerogenic phenotype through upregulation of pathways involved in adipocyte differentiation. While activation of the Wnt/ß-catenin pathway in cDC1 DCs induces IL-10 production, upregulation of the PPARγ pathway in cDC2 DCs directly suppresses their activation. Combined, they promote an anti-inflammatory milieu in vivo delaying the onset of obesity-induced chronic inflammation and insulin resistance. Under long-term over-nutrition, changes in adipocyte biology curtail ß-catenin and PPARγ activation, contributing to VAT inflammation.