Recent insights into the implications of metabolism in plasmacytoid dendritic cell innate functions: Potential ways to control these functions

Abstract

There are more and more data concerning the role of cellular metabolism in innate immune cells, such as macrophages or conventional dendritic cells. However, few data are available currently concerning plasmacytoid dendritic cells (PDC), another type of innate immune cells. These cells are the main type I interferon (IFN) producing cells, but they also secrete other pro-inflammatory cytokines (e.g., tumor necrosis factor or interleukin [IL]-6) or immunomodulatory factors (e.g., IL-10 or transforming growth factor-β). Through these functions, PDC participate in antimicrobial responses or maintenance of immune tolerance, and have been implicated in the pathophysiology of several autoimmune diseases. Recent data support the idea that the glycolytic pathway (or glycolysis), as well as lipid metabolism (including both cholesterol and fatty acid metabolism) may impact some innate immune functions of PDC or may be involved in these functions after Toll-like receptor (TLR) 7/9 triggering. Some differences may be related to the origin of PDC (human versus mouse PDC or blood-sorted versus FLT3 ligand stimulated-bone marrow-sorted PDC). The kinetics of glycolysis may differ between human and murine PDC. In mouse PDC, metabolism changes promoted by TLR7/9 activation may depend on an autocrine/paracrine loop, implicating type I IFN and its receptor IFNAR, explaining a delayed glycolysis. Moreover, PDC functions can be modulated by the metabolism of cholesterol and fatty acids. This may occur via the production of lipid ligands that activate nuclear receptors (e.g., liver X receptor [LXR]) in PDC or through limiting intracellular cholesterol pool size (by statins or LXR agonists) in these cells. Finally, lipid-activated nuclear receptors ( i.e., LXR or peroxisome proliferator activated receptor) may also directly interact with pro-inflammatory transcription factors, such as NF-κB. Here, we discuss how glycolysis and lipid metabolism may modulate PDC functions and how this may be harnessed in pathological situations where PDC play a detrimental role.

Protective effects of delayed intraventricular TLR7 agonist administration on cerebral white and gray matter following asphyxia in the preterm fetal sheep

“…We are unsure as to the mechanistic basis for elevated glucose and lactate levels following completion of GDQ administration. Concerning lactate elevation, the endosomal TLR7 pathway, at least in human blood-derived plasmacytoid dendritic cells, promotes early glycolysis (within minutes following TLR7 stimulation), as supported by elevated rates of lactate efflux 82 . Glycolysis is favored during hypoxia, thus TLR7 stimulation may further enhance this response.…”

How Viral and Intracellular Bacterial Pathogens Reprogram the Metabolism of Host Cells to Allow Their Intracellular Replication

“…On the other hand, also host-detrimental and pro-bacterial effects, especially by IFN-I, have been observed depending on the IBP, the host and the route of infection (Perry et al, 2005; Kearney et al, 2013; Dussurget et al, 2014; McNab et al, 2015; Boxx and Cheng, 2016; Kovarik et al, 2016; Snyder et al, 2017). IFN-mediated events directly affecting the host cell and/or the intracellular IBP metabolism and thereby leading to pro- or anti-microbial effects have hardly been reported and will not be discussed here in detail (Mellor and Munn, 2004; Burke et al, 2014; Chacko et al, 2014; Maggio et al, 2015; York et al, 2015; Fritsch and Weichhart, 2016; Travar et al, 2016; Wu et al, 2016; Saas et al, 2017; Snyder et al, 2017).…”

Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis

“…Altogether, these findings support the hypothesis that an increased lactic acidosis induced by high glycolytic tumor metabolism is involved in the melanoma-mediated pDC collapse. On the other hand, as previously reported, glucose deprivation does not interfere with viability of human pDCs, whereas glycolysis is an essential metabolic pathway for pDCs to execute innate immune functions (e.g., IFN-α secretion) [ 68 , 69 ], suggesting that nutrient deprivation or glycolysis inhibition could impair pDC function in MM. Like many other cancer types, rapidly proliferating melanoma cells utilize aerobic glycolysis at high rates.…”