DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway

Alexaki, Vasileia Ismini; Fodelianaki, Georgia; Neuwirth, Aleš; Mund, C.; Kourgiantaki, Alexandra; Ieronimaki, E; Lyroni, Konstantina; Troullinaki, Maria; Fujii, Chika; Kanczkowski, Waldemar; Ziogas, Athanassios; Peitzsch, Mirko; Großklaus, Sylvia; Sönnichsen, Birte; Gravanis, Achille; Bornstein, Stefan R.; Charalampopoulos, Ioannis; Tsatsanis, Christos; Chavakis, Triantafyllos

doi:10.1038/mp.2017.167

Cited by 73 publications

(87 citation statements)

References 78 publications

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“…Eight to twelve-week-old male C57BL/6 mice (purchased from Janvier Labs, Le Genest-Saint-Isle, France) were injected i.p. with 2 mg DHEA (Sigma-Aldrich, Munich, Germany) diluted in PBS containing 4.5% ethanol and 1% BSA or the same amount of control vehicle diluent (4.5% ethanol, 1% BSA in PBS), as previously described (37). Thirty minutes after DHEA injection, 50 ng of LPS (Escherichia coli O111:B4; Sigma-Aldrich) were injected intrascrotally.…”

Section: Intravital Microscopy Of the Cremaster Musclementioning

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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Section: Intravital Microscopy Of the Cremaster Musclementioning

confidence: 99%

mentioning

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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“…Microglia cells were isolated from Hif2a-HWT and Hif2a-HKO mice according to previously described protocols (27,28). Bone marrow-derived macrophages (BMDM) were isolated according to previously described protocols (29,30).…”

Section: Cell Culturementioning

confidence: 99%

Hematopoietic hypoxia‐inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis

et al. 2018

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A hallmark of proliferative retinopathies, such as retinopathy of prematurity (ROP), is a pathological neovascularization orchestrated by hypoxia and the resulting hypoxia-inducible factor (HIF)-dependent response. We studied the role of Hif2α in hematopoietic cells for pathological retina neovascularization in the murine model of ROP, the oxygen-induced retinopathy (OIR) model. Hematopoietic-specific deficiency of Hif2α ameliorated pathological neovascularization in the OIR model, which was accompanied by enhanced endothelial cell apoptosis. That latter finding was associated with up-regulation of the apoptosis-inducer FasL in Hif2α-deficient microglia. Consistently, pharmacological inhibition of the FasL reversed the reduced pathological neovascularization from hematopoietic-specific Hif2α deficiency. Our study found that the hematopoietic cell Hif2α contributes to pathological retina angiogenesis. Our findings not only provide novel insights regarding the complex interplay between immune cells and endothelial cells in hypoxia-driven retina neovascularization but also may have therapeutic implications for proliferative retinopathies.-Korovina, I., Neuwirth, A., Sprott, D., Weber, S., Sardar Pasha, S. P. B., Gercken, B., Breier, G., El-Armouche, A., Deussen, A., Karl, M. O., Wielockx, B., Chavakis, T., Klotzsche-von Ameln, A. Hematopoietic hypoxia-inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis.

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“…s7). Because ERK activation has roles in both pro-and anti-inflammatory actions of microglia [58][59][60], we also examined the effect on cAMP response elementbinding protein (CREB), which participates in the anti-inflammatory actions [61]. However, no effect in CREB level or phosphorylation was observed ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Immunoregulation of Microglia M2 polarization is an unrecognized physiological function of α -Synuclein

Stewart

Sheng

et al. 2020

Preprint

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BACKGROUNDMicroglial function is vital for maintaining the health of the brain, and their activation is an essential component of neurodegeneration. It is increasingly recognized that microglia also undergo changes, dependent on the cellular environment, that promote mainly reconstructive and anti-inflammatory functions, i.e. mostly desirable functions of microglia in a physiological state. What maintains microglia at this physiological state is essentially unknown, despite significant research on factors that provoke “reactive” or “inflammatory” phenotypes in conditions of injury or disease. One such factor, exposure to the aggregated or oligomeric forms of α-synuclein, an abundant brain protein, plays an essential role in driving microglial activation; including chemotactic migration and production of inflammatory mediators in Lewy body (LB) diseases such as Parkinson’s disease.METHODSIn this study, using in vitro and in vivo models, we challenged primary microglia or BV2 microglia with LPS + IFN-γ,IL-4 + IL-13, α-synuclein monomer and α-synuclein oligomer, examined microglia phenotype and the underlying mechanism by RT-PCR, Western blot, ELISA, IF, IHC, Co-IP. RESULTS: We described a novel physiological function of α-synuclein, in which it modulates microglia towards an anti-inflammatory phenotype by interaction with extracellular signal-regulated kinase (ERK) and recruitment of the ERK, nuclear factor kappa B (NF-κB), and peroxisome proliferator-activated receptor γ (PPARγ) pathways. CONCLUSIONS: These findings suggest a previously unrecognized function of α-synuclein that likely gives new insights into the pathogenesis and potential therapies for Lewy body-related diseases and beyond, given the abundance and multiple functions of α-synuclein in brain tissue.

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DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway

Cited by 73 publications

References 78 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

Hematopoietic hypoxia‐inducible factor 2α deficiency ameliorates pathological retinal neovascularization via modulation of endothelial cell apoptosis

Immunoregulation of Microglia M2 polarization is an unrecognized physiological function of α -Synuclein

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