HIF1\u03b1 activation in dendritic cells under sterile conditions promotes an anti-inflammatory phenotype through accumulation of intracellular lipids

Elizabeth G Wood,Jesmond Dalli,Federica Marelli-Berg,Marc Clément,Claire E Macdougall,Romain A Colas,M Paula Longhi,Hazel Blythe

doi:10.1038/s41598-020-77793-6

Abstract

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.

Highlights

Obesity is among the leading causes of elevated cardiovascular disease mortality and morbidity
Adipocyte expansion decreases oxygen tension and reactive oxidase species (ROS) production, which leads to rapid activation of HIF1α13,14. Classical dendritic cells (cDCs) are present in visceral adipose tissue (VAT) where they control tissue homeostasis[15]
Production of IL-17 in VAT-infiltrated T cells was increased in Hif1α−/− compared to WT mice together with increased IFNγ production in lymph nodes (LN) (Fig. 1d; Suppl Fig. S1d)

Summary

Introduction

Obesity is among the leading causes of elevated cardiovascular disease mortality and morbidity. 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 adiposetissue inflammation and atherosclerotic plaque formation in a mouse model of obesity. Classical dendritic cells (cDCs) are the main antigen presenting cells and key regulators of immune homeostasis and immunity[1]. HIF1α has pleiotropic effects regulating hundreds of genes encoding glycolytic enzymes, glucose transporters, matrix metalloproteinases, angiogenic and survival factors, that may depend on time and context. These divergent reports may be explained by differences in experimental conditions or cell type targeted

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Conclusion