Adipose Recruitment and Activation of Plasmacytoid Dendritic Cells Fuel Metaflammation

Abstract

In obese individuals, visceral adipose tissue (VAT) is the seat of chronic low-grade inflammation (metaflammation), but the mechanistic link between increased adiposity and metaflammation largely remains unclear. In obese individuals, deregulation of a specific adipokine, chemerin, contributes to innate initiation of metaflammation by recruiting circulating plasmacytoid dendritic cells (pDCs) into VAT through chemokine-like receptor 1 (CMKLR1). Adipose tissue-derived high-mobility group B1 (HMGB1) protein activates Toll-like receptor 9 (TLR9) in the adipose-recruited pDCs by transporting extracellular DNA through receptor for advanced glycation end products (RAGE) and induces production of type I interferons (IFNs). Type I IFNs in turn help in proinflammatory polarization of adipose-resident macrophages. IFN signature gene expression in VAT correlates with both adipose tissue and systemic insulin resistance (IR) in obese individuals, which is represented by ADIPO-IR and HOMA2-IR, respectively, and defines two subgroups with different susceptibility to IR. Thus, this study reveals a pathway that drives adipose tissue inflammation and consequent IR in obesity.

Evidence of an anti-inflammatory toll-like receptor 9 (TLR 9) pathway in adipocytes

“…Our data complement recent studies by Revelo et al and Ghosh et al who found that TLR9 expression and activation in particular in visceral adipose tissue led to proinflammatory changes during obesity and were associated with insulin resistance (Ghosh et al 2016, Revelo et al 2016. In this context, it is remarkable that we found increased levels of TLR9 in visceral fat stores of obese patients that did not (yet) suffer from diabetes mellitus, potentially indicating an early event in the development of insulin resistance and diabetes mellitus.…”

“…Recent studies have hinted at an important role of TLR9 signaling in obesity, glucose intolerance and insulin resistance. In this context, TLR9 signaling in the visceral adipose tissue depot in particular seems to play a key role (Hong et al 2015, Ghosh et al 2016, Nishimoto et al 2016, Revelo et al 2016. However, the extent in which individual cell types within the complex adipose tissue microenvironment contribute to the observed effects remains elusive (Apostolopoulos et al 2016).…”

“…TLR9 has recently been postulated to play a role in obesity and insulin resistance (Hong et al 2015, Ghosh et al 2016, Nishimoto et al 2016. Insulin resistance has been associated to inflammatory changes in particular within the visceral adipose tissue compartment (Hardy et al 2012, Ghosh et al 2016, Revelo et al 2016.…”

“…Recently, it has been shown that cell-free DNA (cfDNA) derived from apoptotic adipocytes and so-called extracellular traps (ETs) derived from macrophages and neutrophil granulocytes are increased in serum in murine obesity models as well as in human obese patients (Nishimoto et al 2016, Revelo et al 2016. cfDNA and ETs induce a TLR9-dependent pro-inflammatory transformation of visceral adipose tissue depots, which is mediated via adipose tissue-resident macrophages and liver-resident plasmacytoid dendritic cells (Ghosh et al 2016, Revelo et al 2016. TLR9-dependent production of interleukin-1β (IL-1β) by Kupffer cells induces hepatic steatosis, inflammation and fibrosis in mice fed a cholinedeficient amino acid-defined (CDAA) diet, a murine model of non-alcoholic steatohepatitis (NASH).…”

Macrophage functions in lean and obese adipose tissue

“…It recruits plasmacytoid dendritic cells into visceral adipose tissue, which upon activation secrete type I interferons that promote proinflammatory macrophage polarization 165 . Obese patients have increased chemerin, with associated inflammatory adipokine secretion and adipose tissue metabolic dysfunction 166 .…”