In vitro and in vivo Effects of Lactate on Metabolism and Cytokine Production of Human Primary PBMCs and Monocytes

Abstract

Lactate, the end product of anaerobic glycolysis, is produced in high amounts by innate immune cells during inflammatory activation. Although immunomodulating effects of lactate have been reported, evidence from human studies is scarce. Here we show that expression of genes involved in lactate metabolism and transport is modulated in human immune cells during infection and upon inflammatory activation with TLR ligands in vitro, indicating an important role for lactate metabolism in inflammation. Extracellular lactate induces metabolic reprogramming in innate immune cells, as evidenced by reduced glycolytic and increased oxidative rates of monocytes immediately after exposure to lactate. A short-term infusion of lactate in humans in vivo increased ex vivo glucose consumption of PBMCs, but effects on metabolic rates and cytokine production were limited. Interestingly, long-term treatment with lactate ex vivo, reflecting pathophysiological conditions in local microenvironments such as tumor or adipose tissue, significantly modulated cytokine production with predominantly anti-inflammatory effects. We found time- and stimuli-dependent effects of extracellular lactate on cytokine production, further emphasizing the complex interplay between metabolism and immune cell function. Together, our findings reveal lactate as a modulator of immune cell metabolism which translates to reduced inflammation and may ultimately function as a negative feedback signal to prevent excessive inflammatory responses.

Involvement of Lactate and Pyruvate in the Anti-Inflammatory Effects Exerted by Voluntary Activation of the Sympathetic Nervous System

“…Both lactate and pyruvate have been demonstrated previously to exert anti-inflammatory effects. For instance, very recent work demonstrates that addition of lactate to LPS-stimulated primary human monocytes causes a distinct metabolic shift by decreasing aerobic glycolysis and increasing oxidative phosphorylation, a metabolic state characteristic for anti-inflammatory responses [ 24 ]. In the same study, lactate was shown to decrease LPS-induced production of pro-inflammatory cytokines by human PBMCs [ 24 ].…”

“…For instance, very recent work demonstrates that addition of lactate to LPS-stimulated primary human monocytes causes a distinct metabolic shift by decreasing aerobic glycolysis and increasing oxidative phosphorylation, a metabolic state characteristic for anti-inflammatory responses [ 24 ]. In the same study, lactate was shown to decrease LPS-induced production of pro-inflammatory cytokines by human PBMCs [ 24 ]. The authors proposed that immunomodulatory effects of lactate may serve as a feedback signal to limit excessive inflammatory responses of highly glycolytic pro-inflammatory immune cells [ 24 ].…”

“…In the same study, lactate was shown to decrease LPS-induced production of pro-inflammatory cytokines by human PBMCs [ 24 ]. The authors proposed that immunomodulatory effects of lactate may serve as a feedback signal to limit excessive inflammatory responses of highly glycolytic pro-inflammatory immune cells [ 24 ]. Pyruvate has been shown to decrease mRNA expression and protein levels of pro-inflammatory cytokines TNFα and IL-6 in LPS-stimulated canine PBMCs, whereas IL-10 expression and production was increased [ 25 ].…”

Gut microbiota differences between psoriatic arthritis and undifferentiated arthritis patients

“…Its role in lactic acid metabolism and its links to PSA have yet to be clarified, but its role in PSA patients, compared to undifferentiated arthritis patients, has been demonstrated in our study for the first time. In the future, additional study concerning the immune-modulation, glycobiology (22), and inflammation effect (23) of Megasphaera elsdenii is required to establish the relationship between this organism and PSA disease.…”

Metabolite Transporters as Regulators of Immunity

“…This is especially remarkable and somehow surprising, as HIF1α is usually considered a pro-inflammatory mediator [ 96 ]. Importantly, studies with primary human monocytes and peripheral blood mononuclear cells have confirmed these observations to be relevant for human macrophages biology as well [ 97 ]. Overall, lactate import in macrophages seems to limit their pro-inflammatory potential.…”