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Plasmacytoid dendritic cells (pDCs) play a crucial role in innate viral immunity as the most potent producers of type I interferons (IFN) in the human body. However, the metabolic regulation of IFN production in such vast quantity remains poorly understood. In this study, AMP-activated protein kinase (AMPK) is strongly implicated as a driver of metabolic reprogramming that the authors and others have observed in pDCs after activation via TLR7/9. Oxygen consumption and mitochondrial membrane potential (MMP) were elevated following stimulation of pDCs with influenza or herpes simplex virus. Blocking these changes using mitochondrial inhibitors abrogated IFN-production. While it appears that multiple carbon sources can be used by pDCs, blocking pyruvate metabolism had the strongest effect on IFN-production. Furthermore, we saw no evidence of aerobic glycolysis (AG) during pDC activation and blocking lactate dehydrogenase activity did not inhibit IFN-. TLR7/9 ligation induces a posttranslational modification in Raptor that is catalyzed by AMPK, and blocking TLR7/9 before virus introduction prevents this change. Finally, it is demonstrated that Dorsomorphin, an AMPK inhibitor, inhibited both IFNproduction and MMP in a dose-dependent manner. Taken together, these data reveal a potential cellular mechanism for the metabolic reprogramming in TLR 7/9-activated pDCs that supports activation and IFN-production.

(Fig 1, top). The number of active eccrine sweat glands in the central axilla approximates 175/sq cm, slightly more than in the skin of the forearm.1 Fewer glands are found in the poles of the axilla, however, where there is an associated thinning of the subcutis (Fig 2).

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