Production of IL-6 and Phagocytosis Are the Most Resilient Immune Functions in Metabolically Compromised Human Monocytes

Krauß, Pierre-Louis; Pfeiffenberger, Moritz; Damerau, Alexandra; Buttgereit, Thomas; Chen, Yuling; Gaber, Timo; Buttgereit, Frank

doi:10.3389/fimmu.2021.730672

Cited by 5 publications

(4 citation statements)

References 57 publications

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“…Our results indicate that primary human skin MCs are different from other types of MCs and cell lines in several aspects. First, we found that the OCR of human skin MCs was about half as high as others have found for BMMCs [ 21 , 27 ], but at the same level as human monocytes and twice as high as that of human CD4+ T-cells, as shown by our recent work [ 28 , 29 ]. It can be assumed that OCR levels may be associated with the cell population size and mitochondrial content.…”

Section: Discussionsupporting

confidence: 80%

“…Human skin MCs were incubated in a glucose-free RPMI medium in the presence of myxothiazol or rotenone. Afterward, cells were stained with DAPI (BD Pharmingen, catalogue number 559,925, dilution 1:20) according to the manufacturer’s instructions and as recently described [ 28 ]. Data were acquired using a BD FACS Canto™ II (BD Biosciences, San Jose, CA, USA) and processed by FlowJo v7.6.5 (BD Biosciences, San Jose, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of Complex I of the Respiratory Chain, but Not Complex III, Attenuates Degranulation and Cytokine Secretion in Human Skin Mast Cells

Buttgereit

Pfeiffenberger

Frischbutter

et al. 2022

IJMS

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The mechanisms of mast cell (MC) degranulation and MC-driven skin symptoms are well-described. In contrast, data about the role of mitochondrial respiration for immune functions of human skin MCs are lacking. Oxygen consumption rate (OCR) in primary human skin MCs during IgE-mediated activation in the absence of glucose was examined using a metabolic flux analyzer. Effects of the inhibition of mitochondrial complex I (by rotenone A) and III (by myxothiazol) on degranulation and cytokine secretion (IL-4, IL-5, IL-6, IL-13, TNF-α, and GM-CSF) were explored by the β-hexosaminidase release assay and multiplex ELISA. IgE-mediated activation rapidly increased the mitochondrial OCR and extracellular acidification; the contribution of non-mitochondrial oxygen consumption remained unchanged at lower levels. Both myxothiazol and rotenone A reduced OCR, the mitochondrial parameters, and extracellular acidification; however, myxothiazol did not affect degranulation and cytokine secretion. In contrast, degranulation and the secretion of IL-6, IL-13, TNF-α, and GM-CSF were reduced by rotenone A, whereas the secretion of IL-4 and IL-5 was not significantly affected. The inhibitors did not affect cell viability. Our results highlight the important role played by mitochondrial respiration in primary human skin MCs and allow for a conclusion on a hierarchy of their effector functions. Drugs targeting specific pathways in mitochondria may provide future options to control MC-driven skin symptoms.

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Section: Discussionsupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Inhibition of Complex I of the Respiratory Chain, but Not Complex III, Attenuates Degranulation and Cytokine Secretion in Human Skin Mast Cells

Buttgereit

Pfeiffenberger

Frischbutter

et al. 2022

IJMS

Self Cite

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“…Our exploratory evaluation of the mitochondrial metabolism showed a tendency of AH to increase basal mitochondrial metabolism, seemingly linked to energetic request, ATP production being necessary to support phagocytosis and cytokine production, as recently described 59 . It also showed that AH and vaccine impaired both the maximal respiratory capacity of mitochondria, probably in accordance with increasing proton leak, and spare respiratory capacity assessing mitochondrial reserve.…”

Section: Discussionsupporting

confidence: 66%

Advances on the early cellular events occurring upon exposure of human macrophages to aluminum oxyhydroxide adjuvant

Masson

Badran

Domdom

et al. 2023

Sci Rep

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Aluminum compounds are the most widely used adjuvants in veterinary and human vaccines. Despite almost a century of use and substantial advances made in recent decades about their fate and biological effects, the exact mechanism of their action has been continuously debated, from the initial “depot-theory” to the direct immune system stimulation, and remains elusive. Here we investigated the early in vitro response of primary human PBMCs obtained from healthy individuals to aluminum oxyhydroxide (the most commonly used adjuvant) and a whole vaccine, in terms of internalization, conventional and non-conventional autophagy pathways, inflammation, ROS production, and mitochondrial metabolism. During the first four hours of contact, aluminum oxyhydroxide particles, with or without adsorbed vaccine antigen, (1) were quickly recognized and internalized by immune cells; (2) increased and balanced two cellular clearance mechanisms, i.e. canonical autophagy and LC3-associated phagocytosis; (3) induced an inflammatory response with TNF-α production as an early event; (4) and altered mitochondrial metabolism as assessed by both decreased maximal oxygen consumption and reduced mitochondrial reserve, thus potentially limiting further adaptation to other energetic requests. Further studies should consider a multisystemic approach of the cellular adjuvant mechanism involving interconnections between clearance mechanism, inflammatory response and mitochondrial respiration.

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“…This could be a mechanism of adaptation to the metabolically challenging environment. Such compensatory mechanisms have already been described in monocytes, in which IL6 production is quickly restored after depriving monocytes of ATP and glucose ( 13 ).…”

Section: Discussionmentioning

confidence: 69%

Perspective on direction of control: Cellular metabolism and macrophage polarization

et al. 2022

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Macrophages are innate immune cells with high phenotypic plasticity. Depending on the microenvironmental cues they receive, they polarize on a spectrum with extremes being pro- or anti-inflammatory. As well as responses to microenvironmental cues, cellular metabolism is increasingly recognized as a key factor influencing macrophage function. While pro-inflammatory macrophages mostly use glycolysis to meet their energetic needs, anti-inflammatory macrophages heavily rely on mitochondrial respiration. The relationship between macrophage phenotype and macrophage metabolism is well established, however its precise directionality is still under question. Indeed, whether cellular metabolism per se influences macrophage phenotype or whether macrophage polarization dictates metabolic activity is an area of active research. In this short perspective article, we sought to shed light on this area. By modulating several metabolic pathways in bone marrow-derived macrophages, we show that disruption of cellular metabolism does per se influence cytokine secretion profile and expression of key inflammatory genes. Only some pathways seem to be involved in these processes, highlighting the need for specific metabolic functions in the regulation of macrophage phenotype. We thus demonstrate that the intact nature of cellular metabolism influences macrophage phenotype and function, addressing the directionality between these two aspects of macrophage biology.

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Production of IL-6 and Phagocytosis Are the Most Resilient Immune Functions in Metabolically Compromised Human Monocytes

Cited by 5 publications

References 57 publications

Inhibition of Complex I of the Respiratory Chain, but Not Complex III, Attenuates Degranulation and Cytokine Secretion in Human Skin Mast Cells

Inhibition of Complex I of the Respiratory Chain, but Not Complex III, Attenuates Degranulation and Cytokine Secretion in Human Skin Mast Cells

Advances on the early cellular events occurring upon exposure of human macrophages to aluminum oxyhydroxide adjuvant

Perspective on direction of control: Cellular metabolism and macrophage polarization

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