Angeloni, Elisa and Germelli, Lorenzo and Marchetti, Laura and Da Pozzo, Eleonora and Tremolanti, Chiara and Wetzel, Christian H. and Baglini, Emma and Taliani, Sabrina and Da Settimo, Federico and Martini, Claudia and Costa, Barbara (2023) The human microglial surveillant phenotype is preserved by de novo neurosteroidogenesis through the control of cholesterol homeostasis: Crucial role of 18 kDa Translocator Protein. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 1869 (6): 166751. ISSN 0925-4439, 1879-260X
Full text not available from this repository. (Request a copy)Abstract
Neurodegenerative disease-associated microglia commonly exhibit harmful cholesterol accumulation that impairs their ability to resolve the neuroinflammatory response, contributing to disease onset and progression. Neurosteroids, whose levels have been often found significantly altered in brain diseases, are the most potent endogenous anti-inflammatory molecules exerting beneficial effects on activities of brain cells, including microglia. For the first time, the impact of neurosteroidogenesis on cholesterol homeostasis for the immune surveillance phenotype maintenance was investigated in a human microglia in vitro model. To enhance and inhibit neurosteroidogenesis, pharmacological stimulation and knock-down of 18 kDa Translocator Protein (TSPO), which is involved in the neurosteroidogenesis rate-limiting step, were used as experimental approaches, respectively. The obtained results point to an essential autocrine control of neurosteroidogenesis in orchestrating cholesterol trafficking in human microglia. TSPO pharmacological stimulation ensured cholesterol turnover by strengthening cholesterol efflux systems and preserving healthy immune surveillant phenotype. Conversely, TSPO knock-down induced an impairment of the controlled interplay among cholesterol synthesis, efflux, and metabolism mechanisms, leading to an excessive cholesterol accumulation and acquisition of a chronically activated dysfunctional phenotype. In this model, the exogenous neurosteroid administration restored proper the cholesterol clearance. The TSPO ability in promoting native neurosteroidogenesis opens the way to restore cholesterol homeostasis, and thus to maintain microglia proper functionality for the treatment of neuroinflammation-related brain diseases.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | APOLIPOPROTEIN-E; MOUSE MODEL; TSPO; GENE; DISEASE; EFFLUX; LIGAND; BRAIN; ETIFOXINE; MECHANISM; de novo neurosteroidogenesis; 18 kDa Translocator Protein; Cholesterol homeostasis; Surveillant microglia; Autocrine regulation; TSPO ligand |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie > Molekulare Neurowissenscahften |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 12:09 |
| Last Modified: | 30 Jan 2024 12:09 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60175 |
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