Metabolic Control of Dendritic Cell Functions: Digesting Information

Abstract

Dendritic cells (DCs) control innate and adaptive immunity by patrolling tissues to gather antigens and danger signals derived from microbes and tissue. Subsequently, DCs integrate those environmental cues, orchestrate immunity or tolerance, and regulate tissue homeostasis. Recent advances in the field of immunometabolism highlight the notion that immune cells markedly alter cellular metabolic pathways during differentiation or upon activation, which has important implications on their functionality. Previous studies showed that active oxidative phosphorylation in mitochondria is associated with immature or tolerogenic DCs, while increased glycolysis upon pathogen sensing can promote immunogenic DC functions. However, new results in the last years suggest that regulation of DC metabolism in steady state, after immunogenic activation and during tolerance in different pathophysiological settings, may be more complex. Moreover, ontogenically distinct DC subsets show different functional specializations to control T cell responses. It is, thus, relevant how metabolism influences DC differentiation and plasticity, and what potential metabolic differences exist among DC subsets. Better understanding of the emerging connection between metabolic adaptions and functional DC specification will likely allow the development of therapeutic strategies to manipulate immune responses.

Dynamic metabolic reprogramming in dendritic cells: an early response to influenza infection that is essential for effector function

“…a mean difference of −6.680 mg/dl glucose with 95% CI [-12.24, −1.115]) (Fig 3B). Further, when glucoses derived pyruvate is lacking DC are known to shift to glutaminolysis to fuel TCA cycle to support OXPHOS [19, 58-62]. Thus, even though we find IAV infection results in significant increases in DC glycolysis it appears to uncouple from the TCA cycle, via reduced pyruvate dehydrogenase, concomitant to a modest increase in glutaminolysis acting to fuel OXPHOS related oxygen consumption without evidence of mitochondrial damage as measured by FCCP response and coupling efficiency.…”

Targeting immunometabolism as an anti-inflammatory strategy

“…Warburg first reported on the metabolic shift observed in cancer cells which have a high glucose dependency and increased rate of glycolysis leading to the majority of glucose being metabolized into lactate, even in the presence of oxygen. 98 We have since learned that this phenomenon, named the 'Warburg effect', also occurs in activated immune cells such as M1 macrophages, B cells, NK cells, DCs and Th17 cells, 99,100 making it an attractive therapeutic target in cancer as well as inflammatory disease.…”

Fueling influenza and the immune response: Implications for metabolic reprogramming during influenza infection and immunometabolism

“…[186][187][188][189] Seminal papers in the field delineated changes in glycolysis and/or mitochondrial respiration following TLR stimulation of DCs [189][190][191][192] that are detailed elsewhere. [193][194][195][196][197] Briefly, resting BMDCs produce ATP without substantial anabolism using low levels of glycolysis and FAO to fuel OXPHOS. 28,192 In contrast, TLR-activated BMDCs increase glycolysis and pyruvate is either converted to lactate or acetyl-CoA that enters the TCA cycle to produce TCA intermediates and ATP via OXPHOS.…”