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

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-indiv...

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Autores principales: Karan, Kalpita Rashmi, Trumpff, Caroline, McGill, Marlon A., Thomas, Jacob E., Sturm, Gabriel, Lauriola, Vincenzo, Sloan, Richard P., Rohleder, Nicolas, Kaufman, Brett A., Marsland, Anna L., Picard, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561023/
https://www.ncbi.nlm.nih.gov/pubmed/33073254
http://dx.doi.org/10.1016/j.bbih.2020.100080
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author Karan, Kalpita Rashmi
Trumpff, Caroline
McGill, Marlon A.
Thomas, Jacob E.
Sturm, Gabriel
Lauriola, Vincenzo
Sloan, Richard P.
Rohleder, Nicolas
Kaufman, Brett A.
Marsland, Anna L.
Picard, Martin
author_facet Karan, Kalpita Rashmi
Trumpff, Caroline
McGill, Marlon A.
Thomas, Jacob E.
Sturm, Gabriel
Lauriola, Vincenzo
Sloan, Richard P.
Rohleder, Nicolas
Kaufman, Brett A.
Marsland, Anna L.
Picard, Martin
author_sort Karan, Kalpita Rashmi
collection PubMed
description 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 EC(50)-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.
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spelling pubmed-75610232020-10-15 Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood Karan, Kalpita Rashmi Trumpff, Caroline McGill, Marlon A. Thomas, Jacob E. Sturm, Gabriel Lauriola, Vincenzo Sloan, Richard P. Rohleder, Nicolas Kaufman, Brett A. Marsland, Anna L. Picard, Martin Brain Behav Immun Health Full Length Article 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 EC(50)-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. Elsevier 2020-05-06 /pmc/articles/PMC7561023/ /pubmed/33073254 http://dx.doi.org/10.1016/j.bbih.2020.100080 Text en © 2020 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Full Length Article
Karan, Kalpita Rashmi
Trumpff, Caroline
McGill, Marlon A.
Thomas, Jacob E.
Sturm, Gabriel
Lauriola, Vincenzo
Sloan, Richard P.
Rohleder, Nicolas
Kaufman, Brett A.
Marsland, Anna L.
Picard, Martin
Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood
title Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood
title_full Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood
title_fullStr Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood
title_full_unstemmed Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood
title_short Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood
title_sort mitochondrial respiratory capacity modulates lps-induced inflammatory signatures in human blood
topic Full Length Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561023/
https://www.ncbi.nlm.nih.gov/pubmed/33073254
http://dx.doi.org/10.1016/j.bbih.2020.100080
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