Glucocorticoids coordinate macrophage metabolism through the regulation of the tricarboxylic acid cycle

Stifel, Ulrich; Wolfschmitt, Eva-Maria; Vogt, J.; Wachter, Ulrich; Vettorazzi, Sabine; Tews, Daniel; Hogg, M. I. J.; Zink, Fabian; Koll, Nora Maria; Winning, Sandra; Mounier, Rémi; Chazaud, Bénédicte; Radermacher, Peter; Fischer‐Posovszky, Pamela; Caratti, Giorgio; Tuckermann, Jan

doi:10.1016/j.molmet.2021.101424

Cited by 28 publications

(21 citation statements)

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“…The NRs described herein are pivotal regulators of cellular catabolic metabolism in macrophages (see Table 1, where the known effects NRs specifically on cellular metabolism are listed). While PPARs regulate lipid and cholesterol metabolism, particularly in atherosclerosis, and were long recognised as modulators of myeloid cells and immunity, recent publications have revealed that also other NRs, previously only known to modulate immunity in macrophages through the regulation of cytokines and myeloid activation genes, can use cellular metabolism to achieve their immunoregulatory functions [70,92,113,121,122] (Table 1). Other transcription factors are intimately involved in cellular metabolism, the most prominent being HIF1a, which interacts with NRs, and is a major node in the control of myeloid metabolism by NR.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, as with other NRs, some of these effects were HIF1α dependent. HIF1α stabilisation can retrogradely affect GC actions in macrophages through a mutual regulation by both transcription factors, GR and HIF1α [113]. This demonstrates that the anti‐inflammatory actions of GCs do not only arise from cytokine suppression and induction of anti‐inflammatory genes but also from altering cellular metabolism in myeloid cells, and likely extend to other important functions of these cells, for example phagocytosis and debris clearance.…”

Section: Regulation Of Cellular Metabolism By Gr In Myeloid Cellsmentioning

confidence: 99%

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Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors

2022

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Regulation of cellular catabolic metabolism in immune cells has recently become a major concept for resolution of inflammation. Nuclear receptors (NRs), including peroxisome proliferator activator receptors, 1,25‐dihydroxyvitamin D (3) receptor, liver X receptors, glucocorticoid receptors, oestrogen‐related receptor α and nuclear receptor 4A1, have been identified as major modulators of inflammation, affecting innate immune cells, such as macrophages. Evidence emerges on how NRs regulate cellular metabolism in macrophages during inflammatory processes and contribute to the resolution of inflammation. This could have new implications for our understanding of how NRs shape immune responses and inform anti‐inflammatory drug design. This review will highlight the recent developments about NRs and their role in cellular metabolism in macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Regulation Of Cellular Metabolism By Gr In Myeloid Cellsmentioning

confidence: 99%

Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors

2022

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“…TCA cycle are important to relief in ammation, promote the development of anti-in ammatory function and prevent excessive in ammatory signal transduction [69][70][71]. Recent studies on macrophage biology suggest that TCA cycle remodeling may play an important role in regulating in ammatory factor [72].…”

Section: Discussionmentioning

confidence: 99%

Jingfang Granule Protects Against Concanavalin-A-Induced Immune Hepatitis in Mice Through Regulating Tricarboxylic Acid Cycle

Zhang

Liu

Zhang

et al. 2022

Preprint

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Background Autoimmune hepatitis (AIH) is an autoimmune mediated inflammatory disease that causes serious economic burden to mankind. Previous studies reported that Jingfang Granules (JFG) had an anti-inflammatory effect. However, there are few studies of JFG on AIH. The aim of the study was to investigate the therapeutic effect of JFG on AIH and its mechanisms of action. Methods The animal model of AIH was constructed by intravenous injection of Concanavalin A (Con A). JFG treatment was given by intragastric gavage (ig) after an hour later of injected Con A. Serum and liver tissues were collected after 24 h treatment. Mortality, histology, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in serum were to evaluate therapeutic effect of JFG. The apoptosis of hepatocyte was detected by terminal deoxynucleotidyl transferase mediated dUTP biotin nick end labeling assay (TUNEL). The expression of B-cell lymphoma-2 (Bcl-2), Bcl-2 Associated X (Bax), Cleaved-Caspase 3, Toll-like receptor 4 (TLR4)/nuclear factor kappa B p65 (NF-κB), Mitogen activated protein kinase (MAPK) pathways associated proteins, CS, IDH1, ACLY, SUCLG1, and SUCLA2 were measured by western blot. The inflammatory cytokines interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, interferon (IFN)-γ and anti-inflammatory cytokine interleukin-10 (IL-10) were checked by ELISA. The possible target mechanism of JFG in the treatment of AIH was explored by proteomics and metabolomics. Results The results showed that JFG substantially alleviated Con A-mediated hepatitis in mice, which was shown by increased survival rates, decreased of liver injury, aminotransferase, hepatocyte necrosis, and apoptosis. JFG could also regulate the production of inflammatory factors (IL-1β, IL-4, IL-6, TNF-α, IFN-γ and IL-10) by reduced the activation of TLR4/NF-κB and MAPK pathways. In addition, it was found that JFG could inhibit the inflammatory pathway by regulating tricarboxylic acid (TCA) cycle activity. Conclusions These results suggested that JFG played a therapeutic role in Con A-induced AIH by inhibiting liver injury, apoptosis, and inhibiting inflammatory pathway by regulating TCA cycle.

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“…For S2 cells, mitochondria were stained with Mitotracker for 30 min to detect their morphologies. Mitochondrial morphology was analyzed with Mitochondria Analyzer ( Chaudhry et al, 2020 ), a plugin of Image J software widely used for characterizing mitochondrial morphology in cultured cells ( Mao et al, 2021 ; Stifel et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

RhoA/ROCK Signaling Regulates Drp1-Mediated Mitochondrial Fission During Collective Cell Migration

Ye²,

Kan³

et al. 2022

Front. Cell Dev. Biol.

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Collective migration plays critical roles in developmental, physiological and pathological processes, and requires a dynamic actomyosin network for cell shape change, cell adhesion and cell-cell communication. The dynamic network of mitochondria in individual cells is regulated by mitochondrial fission and fusion, and is required for cellular processes including cell metabolism, apoptosis and cell division. But whether mitochondrial dynamics interplays with and regulates actomyosin dynamics during collective migration is not clear. Here, we demonstrate that proper regulation of mitochondrial dynamics is critical for collective migration of Drosophila border cells during oogenesis, and misregulation of fission or fusion results in reduction of ATP levels. Specifically, Drp1 is genetically required for border cell migration, and Drp1-mediated mitochondrial fission promotes formation of leading protrusion, likely through its regulation of ATP levels. Reduction of ATP levels by drug treatment also affects protrusion formation as well as actomyosin dynamics. Importantly, we find that RhoA/ROCK signaling, which is essential for actin and myosin dynamics during border cell migration, could exert its effect on mitochondrial fission through regulating Drp1’s recruitment to mitochondria. These findings suggest that RhoA/ROCK signaling may couple or coordinate actomyosin dynamics with mitochondrial dynamics to achieve optimal actomyosin function, leading to protrusive and migratory behavior.

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Glucocorticoids coordinate macrophage metabolism through the regulation of the tricarboxylic acid cycle

Cited by 28 publications

References 50 publications

Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors

Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors

Jingfang Granule Protects Against Concanavalin-A-Induced Immune Hepatitis in Mice Through Regulating Tricarboxylic Acid Cycle

RhoA/ROCK Signaling Regulates Drp1-Mediated Mitochondrial Fission During Collective Cell Migration

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