AUTHOR=Basit Farhan , Mathan Till , Sancho David , de Vries I. Jolanda M. 

TITLE=Human Dendritic Cell Subsets Undergo Distinct Metabolic Reprogramming for Immune Response

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02489

DOI=10.3389/fimmu.2018.02489

ISSN=1664-3224

ABSTRACT=<p>Toll-like receptor (TLR) agonists induce metabolic reprogramming, which is required for immune activation. We have investigated mechanisms that regulate metabolic adaptation upon TLR-stimulation in human blood DC subsets, CD1c<sup>+</sup> myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). We show that TLR-stimulation changes expression of genes regulating oxidative phosphorylation (OXPHOS) and glutamine metabolism in pDC. TLR-stimulation increases mitochondrial content and intracellular glutamine in an autophagy-dependent manner in pDC. TLR-induced glutaminolysis fuels OXPHOS in pDCs. Notably, inhibition of glutaminolysis and OXPHOS prevents pDC activation. Conversely, TLR-stimulation reduces mitochondrial content, OXPHOS activity and induces glycolysis in CD1c<sup>+</sup> mDC. Inhibition of mitochondrial fragmentation or promotion of mitochondrial fusion impairs TLR-stimulation induced glycolysis and activation of CD1c<sup>+</sup> mDCs. TLR-stimulation triggers BNIP3-dependent mitophagy, which regulates transcriptional activity of <italic>AMPK</italic>α<italic>1</italic>. BNIP3-dependent mitophagy is required for induction of glycolysis and activation of CD1c<sup>+</sup> mDCs. Our findings reveal that TLR stimulation differentially regulates mitochondrial dynamics in distinct human DC subsets, which contributes to their activation.</p>