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, as well as in tumor immune escape mechanisms. 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. The kinetics of glycolysis after TLR7/9 triggering 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. This could explain a delayed glycolysis in mouse PDC. 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 statin or LXR agonist treatment) 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.

Keywords: LXR; PPAR; cholesterol; fatty acid; glycolysis; immunometabolism; plasmacytoid dendritic cells; type I interferon.

Figure 1.. The main signaling pathways in plasmacytoid dendritic cells that promote metabolic changes or are modulated by metabolic pathways.

This figure summarizes different signaling pathways described in the literature to promote metabolic changes or to be modulated by immunometabolism in plasmacytoid dendritic cells. This includes: endosomal TLR 7 and TLR9, membrane IL-3 receptor (associating CD131 to CD123), GM-CSF receptor (associating CD131 to CD116), and IFN-α receptor (IFNAR associating IFNAR1 and IFNAR2). Only the main pathways with main effector molecules are depicted. For more details, please refer to the main text. Abbreviations (not defined in the main text): IFIG, IFN-I-induced genes; nfκB1, NF-κB gene.

Figure 2.. Metabolic changes in plasmacytoid dendritic cells (PDC) providing energy and affecting their innate immune functions: glycolysis versus fatty acid oxidation coupled with OXPHOS.

( A) The endosomal TLR7 pathway in human blood-derived PDC promotes early glycolysis (within minutes following TLR7 triggering; green font and green arrows), as attested by increased ECAR (extracellular acidification rate; a reflection of lactate excretion). This implicates the HIF-1α molecule that increases the GLUT1 glucose transporter expression allowing extracellular glucose entry. HIF-1α stimulates some enzymes involved in glycolysis (HK or PFK). Glycolysis in human PDC is required for TLR7-induced type I IFN production. A potential link with the activation of the mTORC1 complex (orange arrows) can be seen, since this complex is activated by the endosomal TLR7 pathway and induces HIF-1α in human PDC. Inhibitors of mTORC1 (RAP.), of TLR7 signaling (chlor.), and of glycolysis (2-DG) are written in blue font. All these inhibitors block TLR7-induced type I IFN production. ( B) The TLR9 pathway in mouse bone marrow-derived PDC promotes late glycolysis (after 24 hours) (grey font and grey arrows) via a type I IFN/IFNAR loop (violet arrows). Through this loop, the TLR9 pathway also promotes fatty acid synthesis, FAO coupled with OXPHOS to generate ATP in a PPARα-dependent mechanism (violet font and violet arrows). This TLR9 pathway implicates the activation of mTORC1 in mouse PDC (orange arrows, as depicted in Figure 2A). Specific inhibitors of fatty acid synthesis (C75), pyruvate entry in the mitochondrion (UK5099), TCA cycle (TOFA) or FAO (etoxomir) are written in blue font and have been used to demonstrate the promotion of fatty acid synthesis, FAO and OXPHOS in TLR9-induced type I IFN production, respectively. For more details, please refer to the main text. Abbreviations (not defined in the main text): HK, hexokinase; PFK, phosphofructokinase; RAP., rapamycin; chlor., chloroquine.

Figure 3.. Cholesterol metabolism controls plasmacytoid dendritic cell (PDC) innate functions.

Activation of the LXR pathway by “physiological” oxidized cholesterol derivatives (oxysterols) or synthetic LXR agonists induces the decrease of PDC intracellular cholesterol content by stimulating cholesterol efflux through ABCA1 cholesterol transporter, inhibiting cholesterol entry by decreasing LDL or VLDL receptor (LDLR and VLDLR, respectively) expression and inhibiting de novo cholesterol biosynthesis (also known as the mevalonate pathway). Cholesterol efflux via ABCA1 requires cholesterol acceptors, such as APOA1, and immature HDL (HDL2/3) to generate mature HDL that transport cholesterol towards the liver. Activation of this LXR pathway inhibits TLR7-induced NF-κB activation and phosphorylation of STAT5 and Akt in response to IL-3 stimulation (green font and green arrows). Inhibition of cholesterol biosynthesis by statins (violet font and arrows) inhibits TLR7/9-induced IRF7 translocation in the nucleus, as well as phosphorylation of p38 kinase, and consequently the production of type I IFN. For more details and abbreviations, please refer to the main text.