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.
Highlights
Intracellular metabolism influences functional properties of immune cells, with high glycolytic rates observed during pro-inflammatory responses [1]
Gene expression of the lactate transporter MCT4 (SLC16A3) is upregulated, whereas LDHB expression is downregulated in peripheral blood mononuclear cells (PBMCs) isolated from patients with acute infections compared with healthy controls (Figure 1A), indicating an important role for lactate metabolism in circulating immune cells during inflammation
LDHA and MCT1 expression were decreased in monocytes stimulated with LPS, but not affected significantly in cells stimulated with Pam3Cys
Summary
Intracellular metabolism influences functional properties of immune cells, with high glycolytic rates observed during pro-inflammatory responses [1]. The end product of the glycolytic route, is produced and secreted in high amounts by innate immune cells upon inflammatory activation [2]. High lactate concentrations in tumor microenvironments are known to alter the phenotype of monocytes and macrophages by decreasing cytokine production and migration [3, 4]. Apart from its role in the tumor microenvironment, immunomodulatory effects of lactate may be relevant in the adipose tissue, where concentrations vary dependent on the metabolic state [5] or in the circulation, where lactate levels are known to fluctuate. Circulating lactate levels range from 0.5 to 2 mM and can increase up to 10 to 25 mM after intense exercise [6, 7] or during pathophysiologic conditions, such as sepsis [8], where plasma lactate levels may increase to levels above 4 mM [9, 10].
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