Immune cell-derived cytokines contribute to obesity-related inflammation, fibrogenesis and metabolic deregulation in human adipose tissue

Charles Caër,Adriana Torcivia,Christine Poitou,Christine Rouault,Karine Clément,Jean-Christophe Bichet,Judith Aron-Wisnewsky,Michèle Guerre-Millo,Tiphaine Le Roy,Sébastien André

doi:10.1038/s41598-017-02660-w

Abstract

Adipose tissue contains a variety of immune cells, which vary in abundance and phenotype with obesity. The contribution of immune cell-derived factors to inflammatory, fibrotic and metabolic alterations in adipose tissue is not well established in human obesity. Human primary adipose tissue cells, including pre-adipocytes, endothelial cells and mature adipocytes, were used to investigate deregulation of cell- and pathway-specific gene profiles. Among factors known to alter adipose tissue biology, we focus on inflammatory (IL-1β and IL-17) and pro-fibrotic (TGF-β1) factors. rIL-1β and rIL-17 induced concordant pro-inflammatory transcriptional programs in pre-adipocytes and endothelial cells, with a markedly more potent effect of IL-1β than IL-17. None of these cytokines had significant effect on fibrogenesis-related gene expression, contrasting with rTGF-β1-induced up-regulation of extracellular matrix components and pro-fibrotic factors. In mature adipocytes, all three factors promoted down-regulation of genes functionally involved in lipid storage and release. IL-1β and IL-17 impacted adipocyte metabolic genes in relation with their respective pro-inflammatory capacity, while the effect of TGF-β1 occurred in face of an anti-inflammatory signature. These data revealed that IL-1β and IL-17 had virtually no effect on pro-fibrotic alterations but promote inflammation and metabolic dysfunction in human adipose tissue, with a prominent role for IL-1β.

Highlights

In obesity, the adipose tissue is a site of immune cell accumulation, which maintains a state of chronic low-grade inflammation in absence of infection
In co-culture experiments using human adipose tissue-derived primary cells, we showed that IL-22 increased the release of IL-1β by macrophages, while IL-1β enhanced the production of Th17 cytokines by autologous CD4+ T cells
The amplitude of IL-17 production by CD4+ T cells was positively correlated with IL-1β concentrations in Omental adipose tissue conditioned media (omCM) (Fig. 1C), supporting the role of adipose tissue IL-1β to trigger IL-17 release by Th17 polarized T cells

Summary

Introduction

The adipose tissue is a site of immune cell accumulation, which maintains a state of chronic low-grade inflammation in absence of infection. In co-culture experiments using human adipose tissue-derived primary cells, we showed that IL-22 increased the release of IL-1β by macrophages, while IL-1β enhanced the production of Th17 cytokines by autologous CD4+ T cells This pro-inflammatory paracrine loop was amplified in type 2 diabetic subjects and attenuated after bariatric surgery-induced weight loss, congruent with variations in blood glycemic variables[25]. At odds with accumulation of Th17 cells in human obesity, IL-17 deficient mice displayed increased adiposity[30] supported by IL-17 anti-adipogenic effect demonstrated in vitro[31] These mouse observations did not unambiguously establish implication of Th17-related cytokines to drive obesity-induced deterioration of adipose tissue biology. The aim of the present study was to explore the contribution of immune cell-derived factors to alter adipose tissue cell biology in humans. We ought to test the capacity of IL-1β, Th17-related cytokines and TGF-β1 to induce inflammation and fibrogenesis and to alter adipocyte metabolic capacity

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Conclusion