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

Frank Vrieling; Xanthe A M H van Dierendonck; Martin Jaeger; Anna W M Janssen; Anneke Hijmans; Mihai G Netea; Cees J Tack; Rinke Stienstra

doi:10.1097/IN9.0000000000000008

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

Immunometabolism (Cobham). 2022 Nov 1;4(4):e00008. doi: 10.1097/IN9.0000000000000008. eCollection 2022 Oct.

Authors

Frank Vrieling¹, Xanthe A M H van Dierendonck^{1

2}, Martin Jaeger², Anna W M Janssen², Anneke Hijmans², Mihai G Netea^{2

3}, Cees J Tack², Rinke Stienstra^{1

2}

Affiliations

¹ Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands.
² Department of Internal Medicine (463) and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.

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.

Keywords: glycolysis; human immune cell function; lactate.