Glycolytic activity in human immune cells: inter-individual variation and functional implications during health and diabetes

Abstract

An increase in glucose uptake driving aerobic glycolysis is a robust hallmark of immune cell activation. The glycolytic response supports functional alterations of the innate immune cells including the production and release of cytokines. Large inter-individual differences in the magnitude of this cytokine response are known to exist. In addition, the presence of disease is known to impact on immune cell function. Whether variation in metabolic responses of immune cells exist between individuals during health or disease is currently unknown. Here, we explore inter-individual differences in the glycolytic rate of immune cells using lactate production as readout upon activation using a variety of different stimuli. Glycolytic responses are subsequently associated to functional immune cell responses in healthy humans. In addition, we determined the glycolytic rate of immune cells and its association with immune function using patients diagnosed with diabetes mellitus. Based on the relative increase in lactate production after activation, distinct clusters of low, intermediate, and high responders could be identified, illustrating the existence of variation in glycolytic responses in healthy subjects. Interestingly, the production of cytokines mirrored these high-, intermediate-, and low-lactate patterns after pathogenic stimulation. In patients with diabetes mellitus, a reduced correlation was found between lactate and cytokine production, specifically for IL-6. Furthermore, based on the relative increase in lactate production, variability in the glycolytic response was reduced compared to healthy subjects. In conclusion, our results show a specific association between the glycolytic rate and function in human immune cells after stimulation with different pathogens. In addition to demonstrating the existence of glycolytic variability and specificity depending on the type of stimulus, the association between glycolysis and function in innate immune cells is altered during the presence of diabetes.

Training vs. Tolerance: The Yin/Yang of the Innate Immune System

“…Other attempts to understand the role of the pentose phosphate pathway (PPP) in trained immunity responses by the pharmacological blockage of this metabolic event demonstrated this pathway as a dispensable occasion [ 161 , 167 , 171 ]. Even though, to date, there have been several papers indicating the crucial role of several metabolic pathways supporting the induction of training effects in innate immune cells, individual metabolic variations (i.e., glycolytic variability in diabetes patients) of the organisms should be taken into consideration since they significantly alter this resistance reaction [ 172 ].…”

Dysregulated cytokine and oxidative response in hyper-glycolytic monocytes in obesity

“…Sex-specific aspects of the proteome of monocytes from donors with overweight and obesity may be addressed in further studies. Regarding the effects on the glycolytic rate, no influence of sex on glycolytic rate of monocytes activated by bacterial stimuli was previously observed ( 65 ). We also cannot completely rule out the influence of age on our results.…”

Adipose tissue immunometabolism: unveiling the intersection of metabolic and immune regulation

“…The precise mechanisms by which energy metabolism is reprogrammed in obese subjects and its relationship with dysfunctional AT have not been fully elucidated. However, observations suggest active involvement of both the glycolytic pathway and FOx 14 . Alongside MCFs, healthy AT also houses other innate immune cells that contribute to maintaining an anti-inflammatory environment.…”

“…Upon stimulation, immune cells rapidly up-regulate glucose uptake and its metabolism to lactate for cell proliferation and pro-inflammatory cytokine production. In human immune cells, the increase in cytokine secretion in response to pathogenic stimulation is proportional to the increase in lactate release 14 . Conversely, fatty acid oxidation is vital for the differentiation and functioning of regulatory T cells (Tregs) and dendritic cells 15,16 .…”