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

Stifel, Ulrich; Caratti, Giorgio; Tuckermann, Jan

doi:10.1002/1873-3468.14474

Cited by 5 publications

(3 citation statements)

References 144 publications

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“…GCs are also highly anti-inflammatory, especially for macrophage function through classical but also metabolic pathways [25][26][27] , and therefore may be involved in the inflammatory response during obesity. We propose that GCs potentially have a dual role during obesity- (1) suppressing inflammatory activation of macrophages in adipose tissue, and (2) promoting lipid accumulation and insulin resistance by acting on adipocytes.…”

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confidence: 99%

Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance

et al. 2023

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Insulin resistance (IR) during obesity is linked to adipose tissue macrophage (ATM)-driven inflammation of adipose tissue. Whether anti-inflammatory glucocorticoids (GCs) at physiological levels modulate IR is unclear. Here, we report that deletion of the GC receptor (GR) in myeloid cells, including macrophages in mice, aggravates obesity-related IR by enhancing adipose tissue inflammation due to decreased anti-inflammatory ATM leading to exaggerated adipose tissue lipolysis and severe hepatic steatosis. In contrast, GR deletion in Kupffer cells alone does not alter IR. Co-culture experiments show that the absence of GR in macrophages directly causes reduced phospho-AKT and glucose uptake in adipocytes, suggesting an important function of GR in ATM. GR-deficient macrophages are refractory to alternative ATM-inducing IL-4 signaling, due to reduced STAT6 chromatin loading and diminished anti-inflammatory enhancer activation. We demonstrate that GR has an important function in macrophages during obesity by limiting adipose tissue inflammation and lipolysis to promote insulin sensitivity.

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confidence: 99%

Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance

et al. 2023

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“…However, some immune aspects in PPARα have been studied in different cell types and systems. Study of PPARα global knockout (KO) mice, which have an increase in cytokine expression in some instances, has suggested an anti-inflammatory role for this protein ( 26 , 27 ). In another study, PPARα-KO mice showed increased helper CD4 + T cell type 17 (Th17) generation resulting in increased pathology of murine experimental autoimmune encephalomyelitis ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor alpha is essential factor in enhanced macrophage immune function induced by angiotensin converting enzyme

Bernstein

2024

Preprint

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An upregulation of angiotensin-converting enzyme (ACE) expression strengthens the immune activity of myeloid lineage cells as a natural functional regulation mechanism in our immunity. ACE10/10 mice, possessing increased ACE expression in macrophages, exhibit enhanced anti-tumor immunity and anti-bactericidal effects compared to those of wild type (WT) mice, while the detailed molecular mechanism has not been elucidated yet. In this report, we demonstrate that peroxisome proliferator-activated receptor alpha (PPARα) is a key molecule in the functional upregulation of macrophages induced by ACE. The expression of PPARα, a transcription factor regulating fatty acid metabolism-associated gene expressions, was upregulated in ACE-overexpressing macrophages. To pinpoint the role of PPARα in the enhanced immune function of ACE-overexpressing macrophages, we established a line with myeloid lineage-selective PPARα depletion employing the Lysozyme 2 (LysM)-Cre system based on ACE 10/10 mice (named A10-PPARα-Cre). Interestingly, A10-PPARα-Cre mice exhibited larger B16-F10-originated tumors than original ACE 10/10 mice. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-overexpressing macrophages, resulting in reduced tumor antigen-specific CD8+ T cell activity. Additionally, the anti-bactericidal effect was also impaired in A10-PPARα-Cre mice, resulting in similar bacterial colonization to WT mice in Methicillin-Resistant Staphylococcus aureus (MRSA) infection. PPARα depletion downregulated phagocytic activity and bacteria killing in ACE-overexpressing macrophages. Moreover, THP-1-ACE-derived macrophages, as a human model, expressing upregulated PPARα exhibited enhanced cytotoxicity against B16-F10 cells and MRSA killing. These activities were further enhanced by the PPARα agonist, WY 14643, while abolished by the antagonist, GW6471, in THP-1-ACE cells. Thus, PPARα is an indispensable molecule in ACE-dependent functional upregulation of macrophages in both mice and humans.

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“…During efferocytosis, there is activation of a molecular switch that drives phenotype and bioenergetics changes in macrophages from M1 (high glycolytic activity) towards M2 (oxidative phosphorylation) to resolve inflammation. The exact mechanism of this phenotype switch is still unclear but is thought to involve the activity of various specialized pro-resolving lipid mediators (SPMs) (such as eicosanoids, lipoxins, resolvins, protectins, maresins) (Ryan & Godson 2010, Börgeson & Godson 2012 and nuclear receptor signalling (PPARγ/α, liver X receptors, glucocorticoid receptors, orphan nuclear receptors (Nur)) (Stifel et al 2022). During this process, lysosomal degradation of apoptotic bodies through catabolism of cell corpses furthermore provides substrates for the metabolic switch to favour oxidative phosphorylation and triggers various nuclear transcription factors to induce the transcription of immunosuppressive cytokines such as IL10 and transforming growth factor-β (Zhang et al 2019b).…”

Section: Monocytes/macrophagesmentioning

confidence: 99%

Immunology of chronic low-grade inflammation: relationship with metabolic function

Vyver

2023

Journal of Endocrinology

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Inflammation is part of the body’s innate immune response and is an essential process that not only defends against harmful bacteria and pathogens but also plays a key role in the maintenance and repair of tissues. Under pathological conditions, there is bilateral crosstalk between immune regulation and aberrant metabolism resulting in persistent inflammation in the absence of infection. This phenomenon is referred to as sterile metabolic inflammation (metainflammation) and occurs if the initiating stimulus is not removed or if the resolution process is disrupted. Disruption of this tightly regulated immune response and its failure to resolve as is evident in metabolic disorders and is not only associated with disease progression but also leads to immune senescence and should not be neglected in the clinical management of patients. This review gives an overview of the mechanisms underlying chronic metabolic inflammation, the aberrant metabolic activation of innate immune cells (neutrophils, macrophages, mast cells, dendritic cells) and its role in disease progression using obesity-diabetes as a prime example. Addressing the underlying subclinical metabolic inflammation in addition to achieving glucose control may contribute significantly towards therapeutic interventions aimed at preventing the onset of co-morbidities in diabetic patients.

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

Cited by 5 publications

References 144 publications

Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance

Glucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance

Peroxisome proliferator-activated receptor alpha is essential factor in enhanced macrophage immune function induced by angiotensin converting enzyme

Immunology of chronic low-grade inflammation: relationship with metabolic function

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