Neurosteroids as regulators of neuroinflammation

Yılmaz, Canelif; Karali, Kanelina; Fodelianaki, Georgia; Gravanis, Achille; Chavakis, Triantafyllos; Charalampopoulos, Ioannis; Alexaki, Vasileia Ismini

doi:10.1016/j.yfrne.2019.100788

Cited by 146 publications

(113 citation statements)

References 345 publications

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“…Dehydroepiandrosterone (DHEA; 5-androsten-3b-hydroxy-17one) and its sulfate ester are abundant circulating steroid hormones in human adults, whereas their concentration declines with age and in inflammatory diseases, such as arthritis and systemic lupus erythematosus (22)(23)(24)(25)(26). In humans, DHEA is produced in the adrenal cortex, the gonads, and the CNS (27)(28)(29)(30). In tissues, DHEA displays anti-inflammatory properties, including inhibition of leukocyte recruitment (31,32).…”

mentioning

confidence: 99%

“…Moreover, it was shown to bind to G protein-coupled receptors in endothelial and neuronal cells (35,36). Additionally, it binds and activates the nerve growth factor (NGF) receptor, tropomyosin-related kinase A (TRKA), in neuronal and microglial cells, thereby triggering downstream AKT signaling (30,37,38). However, its exact mechanisms of action, especially in the context of recruitment regulation, remain largely unknown (39,40).…”

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confidence: 99%

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DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1

Ziogas

Maekawa

Wießner³

et al. 2020

The Journal of Immunology

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Leukocytes are rapidly recruited to sites of inflammation via interactions with the vascular endothelium. The steroid hormone dehydroepiandrosterone (DHEA) exerts anti-inflammatory properties; however, the underlying mechanisms are poorly understood. In this study, we show that an anti-inflammatory mechanism of DHEA involves the regulation of developmental endothelial locus 1 (DEL-1) expression. DEL-1 is a secreted homeostatic factor that inhibits b2-integrin-dependent leukocyte adhesion, and the subsequent leukocyte recruitment and its expression is downregulated upon inflammation. Similarly, DHEA inhibited leukocyte adhesion to the endothelium in venules of the inflamed mouse cremaster muscle. Importantly, in a model of lung inflammation, DHEA limited neutrophil recruitment in a DEL-1-dependent manner. Mechanistically, DHEA counteracted the inhibitory effect of inflammation on DEL-1 expression. Indeed, whereas TNF reduced DEL-1 expression and secretion in endothelial cells by diminishing C/EBPb binding to the DEL-1 gene promoter, DHEA counteracted the inhibitory effect of TNF via activation of tropomyosin receptor kinase A (TRKA) and downstream PI3K/AKT signaling that restored C/EBPb binding to the DEL-1 promoter. In conclusion, DHEA restrains neutrophil recruitment by reversing inflammation-induced downregulation of DEL-1 expression. Therefore, the anti-inflammatory DHEA/DEL-1 axis could be harnessed therapeutically in the context of inflammatory diseases.

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confidence: 99%

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confidence: 99%

DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1

Ziogas

Maekawa

Wießner³

et al. 2020

The Journal of Immunology

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“…Apart from systemic hormonal influence, the CNS is a highly steroidogenic environment synthesizing steroids de novo, as well as metabolizing steroids derived from the circulation. The synthesis of neurosteroids is regulated by neuroinflammation, and on the contrary, several steroids, for example 17β‐estradiol, dehydroepiandrosterone (DHEA), and allopregnanolone, regulate neuroinflammatory responses mediated by microglia …”

Section: Effects Of Sex Hormones On Microgliamentioning

confidence: 99%

“…The synthesis of neurosteroids is regulated by neuroinflammation, and on the contrary, several steroids, for example 17β-estradiol, dehydroepiandrosterone (DHEA), and allopregnanolone, regulate neuroinflammatory responses mediated by microglia. 91 Estrogen, a female sex hormone, is known to have neuroprotective effects. Recent literature provides evidence that estrogens and estrogen receptors are involved with microglial action.…”

Section: Effec Ts Of S E X Hormone S On Microg Liamentioning

confidence: 99%

Sexually dimorphic microglia and ischemic stroke

et al. 2019

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Ischemic stroke kills more women compared with men thus emphasizing a significant sexual dimorphism in ischemic pathophysiological outcomes. However, the mechanisms behind this sexual dimorphism are yet to be fully understood. It is well established that cerebral ischemia activates a variety of inflammatory cascades and that microglia are the primary immune cells of the brain. After ischemic injury, microglia are activated and play a crucial role in progression and resolution of the neuroinflammatory response. In recent years, research has focused on the role that microglia play in this sexual dimorphism that exists in the response to central nervous system (CNS) injury. Evidence suggests that the molecular mechanisms leading to microglial activation and polarization of phenotypes may be influenced by sex, therefore causing a difference in the pro/anti‐inflammatory responses after CNS injury. Here, we review advances highlighting that sex differences in microglia are an important factor in the inflammatory responses that are seen after ischemic injury. We discuss the main differences between microglia in the healthy and diseased developing, adult, and aging brain. We also focus on the dimorphism that exists between males and females in microglial‐induced inflammation and energy metabolism after CNS injury. Finally, we describe how all of the current research and literature regarding sex differences in microglia contribute to the differences in poststroke responses between males and females.

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“…Estrogen was known for many years to be active in the central nervous system (CNS) [see ( 56 , 57 ) for reviews]. They arrive at their target cells either through the general circulation (by crossing the blood-brain barrier-BBB-) or through local production by neurons or astrocytes ( 58 , 59 ).…”

Section: Gper1 Involvement In Immune-related Human Diseasesmentioning

confidence: 99%

G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases

2020

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G protein-coupled estrogen receptor 1 (GPER1), is a functional estrogen receptor involved in estrogen related actions on several systems including processes of the nervous, reproductive, metabolic, cardiovascular, and immune system. Regarding the latter, GPER is expressed in peripheral B and T lymphocytes as well as in monocytes, eosinophils, and neutrophils. Several studies have implicated GPER in immune-mediated diseases like multiple sclerosis, Parkinson’s disease, and atherosclerosis-related inflammation, while a recent report suggests that its deletion could be responsible for a form of familial immunodeficiency. It has also been suggested that it is a key regulator of immune-mediated events in breast, pancreatic, prostate, and hepatocellular cancer as well as in melanoma. GPER has been also reported to interact with classic ER-alpha or its splice variants in order to modify immune functions. This review aims to present current knowledge relating GPER to immune functions, the cellular and signaling pathways involved, as well as the potential clinical implications of GPER modulation in immune-related diseases.

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Neurosteroids as regulators of neuroinflammation

Cited by 146 publications

References 345 publications

DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1

DHEA Inhibits Leukocyte Recruitment through Regulation of the Integrin Antagonist DEL-1

Sexually dimorphic microglia and ischemic stroke

G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases

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