Dynamic modelling predicts lactate and IL-1β as interventional targets in metabolic-inflammation-clock regulatory loop in glioma.

Abstract

In an attempt to understand the role of dysregulated circadian rhythm in glioma, our recent findings highlighted the existence of a feed-forward loop between tumour metabolite lactate, pro-inflammatory cytokine IL-1β and circadian CLOCK. To further elucidate the implication of this complex interplay, we developed a mathematical model that quantitatively describes this lactate dehydrogenase A (LDHA)-IL-1β-CLOCK/BMAL1 circuit and predicts potential therapeutic targets. The model was calibrated on quantitative western blotting data in two glioma cell lines in response to either lactate inhibition or IL-1β stimulation. The calibrated model described the experimental data well and most of the parameters were identifiable, thus the model was predictive. Sensitivity analysis identified IL-1β and LDHA as potential intervention points. Mathematical models described here can be useful to understand the complex interrelationship between metabolism, inflammation and circadian rhythm, and in designing effective therapeutic strategies. Our findings underscore the importance of including the circadian clock when developing pharmacological approaches that target aberrant tumour metabolism and inflammation. Insight box  The complex interplay of metabolism-inflammation-circadian rhythm in tumours is not well understood. Our recent findings provided evidence of a feed-forward loop between tumour metabolite lactate, pro-inflammatory cytokine IL-1β and circadian CLOCK/BMAL1 in glioma. To elucidate the implication of this complex interplay, we developed a mathematical model that quantitatively describes this LDHA-IL-1β-CLOCK/BMAL1 circuit and integrates experimental data to predict potential therapeutic targets. The study employed a multi-start optimization strategy and profile likelihood estimations for parameter estimation and assessing identifiability. The simulations are in reasonable agreement with the experimental data. Sensitivity analysis found LDHA and IL-1β as potential therapeutic points. Mathematical models described here can provide insights to understand the complex interrelationship between metabolism, inflammation and circadian rhythm, and in identifying effective therapeutic targets.