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

Abstract

SummaryVisceral 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/β-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 β-catenin and PPARγ activation, contributing to VAT inflammation.

Properties and functions of adipose tissue macrophages in obesity

“…38,39 Although ATDCs increase quantitatively along with ATMs in obesity, 39,95,96 the contribution of ATDCs to meta-inflammation and IR remains not completely understood. 97 Based on certain reports, human CD11c + CD1c + and mouse CD11c high F4/80 low ATDCs have been considered as an inflammatory subtype of DCs in AT in obesity-associated IR. 39,91 Similarly, an increase in ATDCs has been positively correlated with high BMI in humans.…”

“…In addition, lack of b-catenin in ATDCs is associated with decreased IL-10 levels and suppressed Treg recruitment to AT leading to more inflammation. 97 Based on certain reports, human CD11c + CD1c + and mouse CD11c high F4/80 low ATDCs have been considered as an inflammatory subtype of DCs in AT in obesity-associated IR. 89 In DIO models, a population of CDllc high F4/80 neg ATDCs has been shown to be responsible for the induction of both Th1 and Th17 cells, whereas CDllc high F4/80 low ATDCs for the differentiation of Th17 cells.…”

Immunophenotypic Profiles in Polycystic Ovary Syndrome

“…After receiving the activation signal associated with the antigen, DCs produce cytokines and inflammatory mediators such as TNFα, IL-6, IL-11, IL-12, and IL-23, which, in turn, induce the proliferation of allogeneic T cells and differentiate them to the Th17 and Th1 subtypes [40]. However, in visceral adipose tissue (VAT), DCs suppress inflammation by activating the β-catenin and PPARγ pathways, which are important regulatory mechanisms for fat expansion [41]. Subsequently, β-catenin activation triggers PI3K/Akt that, in turn, induces IL-10 production and inhibits IL-6 secretion [42].…”

Adipose tissue dendritic cells in steady‐state

“…observed increased permeability and vessel fibrosis in CCR7 −/− mice; however, on recovery of CCR7 in cDCs the development of fibrosis was reversed. Antigen sampling is not limited to lymphatic vessels as VAT‐cDCs are also observed in close proximity to blood vessels . These studies suggest that VAT‐cDCs are strategically located close to vessels to sample antigen and maintain vessel integrity, therefore contributing to the immune surveillance of neighbouring tissues.…”

“…VAT‐cDC cross‐talk appears to modulate not only pre‐adipocyte differentiation but also adipocyte function. Our work recently demonstrated that cDCs in VAT acquire a tolerogenic phenotype under physiological conditions by up‐regulating pathways involved in adipocyte differentiation . In VAT, the Wnt/ β ‐catenin pathway keeps pre‐adipocyte differentiation in check, while PPAR γ signalling allows adipocyte expansion to buffer excess of nutrients.…”