Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood

Brain, Behavior, & Immunity - Health

Brett A. Kaufman¹  Richard P. Sloan²  Caroline Trumpff²  Martin Picard²  Gabriel Sturm²  Marlon A. McGill²  Vincenzo Lauriola²  Kalpita Rashmi Karan²  Jacob E. Thomas²  Anna L. Marsland³  Nicolas Rohleder⁴ 

[1] Department of Medicine, Division of Cardiology, University of Pittsburgh, Pittsburgh, PA, United States;Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States;Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States;Institute of Psychology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;

关键词: Mitochondria;    Inflammation;    Human blood;    LPS;    Cytokines;    TNF-α;   

DOI  :  

来源: DOAJ

【 摘 要 】

Mitochondria modulate inflammatory processes in various model organisms, but it is unclear how much mitochondria regulate immune responses in human blood leukocytes. Here, we examine the effect of i) experimental perturbations of mitochondrial respiratory chain function, and ii) baseline inter-individual variation in leukocyte mitochondrial energy production capacity on stimulated cytokine release and glucocorticoid (GC) sensitivity. In a first cohort, whole blood from 20 healthy women and men was stimulated with increasing concentrations of the immune agonist lipopolysaccharide (LPS). Four inhibitors of mitochondrial respiratory chain Complexes I, III, IV, and V were used (LPS ​+ ​Mito-Inhibitors) to acutely perturb mitochondrial function, GC sensitivity was quantified using the GC-mimetic dexamethasone (DEX) (LPS ​+ ​DEX), and the resultant cytokine signatures mapped with a 20-cytokine array. Inhibiting mitochondrial respiration caused large inter-individual differences in LPS-stimulated IL-6 reactivity (Cohen’s d ​= ​0.72) and TNF-α (d ​= ​1.55) but only minor alteration in EC50-based LPS sensitivity (d ​= ​0.21). Specifically, inhibiting mitochondrial Complex IV potentiated LPS-induced IL-6 levels by 13%, but inhibited TNF-α induction by 72%, indicating mitochondrial regulation of the IL-6/TNF-α ratio. As expected, DEX treatment suppressed multiple LPS-induced pro-inflammatory cytokines (IFN-γ, IL-6, IL-8, IL-1β, TNF-α) by >85% and increased the anti-inflammatory cytokine IL-10 by 80%. Inhibiting Complex I potentiated DEX suppression of IL-6 by a further 12% (d ​= ​0.73), indicating partial mitochondrial modulation of glucocorticoid sensitivity. Finally, to examine if intrinsic mitochondrial respiratory capacity may explain a portion of immune reactivity differences across individuals, we measured biochemical respiratory chain enzyme activities and mitochondrial DNA copy number in isolated peripheral blood mononuclear cells (PBMCs) from a second cohort of 44 healthy individuals in parallel with LPS-stimulated IL-6 and TNF-α response. Respiratory chain function, particularly Complex IV activity, was positively correlated with LPS-stimulated IL-6 levels (r ​= ​0.45, p ​= ​0.002). Overall, these data provide preliminary evidence that mitochondrial behavior modulates LPS-induced inflammatory cytokine signatures in human blood.

【 授权许可】

Unknown