De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein
Neuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo. Unexpected...
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| author | Lorenzo Germelli Eleonora Da Pozzo Chiara Giacomelli Chiara Tremolanti Laura Marchetti Christian H. Wetzel Elisabetta Barresi Sabrina Taliani Federico Da Settimo Claudia Martini Barbara Costa |
| author_facet | Lorenzo Germelli Eleonora Da Pozzo Chiara Giacomelli Chiara Tremolanti Laura Marchetti Christian H. Wetzel Elisabetta Barresi Sabrina Taliani Federico Da Settimo Claudia Martini Barbara Costa |
| author_sort | Lorenzo Germelli |
| collection | DOAJ |
| description | Neuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo. Unexpectedly, immortalized murine microglia recently exhibited this de novo biosynthesis; herein, de novo neurosteroidogenesis was characterized in immortalized human microglia. The results demonstrated that C20 and HMC3 microglial cells constitutively express members of the neurosteroidogenesis multiprotein machinery—in particular, the transduceosome members StAR and TSPO, and the enzyme CYP11A1. Moreover, both cell lines produce pregnenolone and transcriptionally express the enzymes involved in neurosteroidogenesis. The high TSPO expression levels observed in microglia prompted us to assess its role in de novo neurosteroidogenesis. TSPO siRNA and TSPO synthetic ligand treatments were used to reduce and prompt TSPO function, respectively. The TSPO expression downregulation compromised the de novo neurosteroidogenesis and led to an increase in StAR expression, probably as a compensatory mechanism. The pharmacological TSPO stimulation the de novo neurosteroidogenesis improved in turn the neurosteroid-mediated release of Brain-Derived Neurotrophic Factor. In conclusion, these results demonstrated that de novo neurosteroidogenesis occurs in human microglia, unravelling a new mechanism potentially useful for future therapeutic purposes. |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6840d420cb9d42f6b87cb8b5d834c2312023-11-21T11:02:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01226311510.3390/ijms22063115De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator ProteinLorenzo Germelli0Eleonora Da Pozzo1Chiara Giacomelli2Chiara Tremolanti3Laura Marchetti4Christian H. Wetzel5Elisabetta Barresi6Sabrina Taliani7Federico Da Settimo8Claudia Martini9Barbara Costa10Department of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Psychiatry and Psychotherapy, Molecular Neurosciences, University of Regensburg, 93053 Regensburg, GermanyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyDepartment of Pharmacy, University of Pisa, 56126 Pisa, ItalyNeuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo. Unexpectedly, immortalized murine microglia recently exhibited this de novo biosynthesis; herein, de novo neurosteroidogenesis was characterized in immortalized human microglia. The results demonstrated that C20 and HMC3 microglial cells constitutively express members of the neurosteroidogenesis multiprotein machinery—in particular, the transduceosome members StAR and TSPO, and the enzyme CYP11A1. Moreover, both cell lines produce pregnenolone and transcriptionally express the enzymes involved in neurosteroidogenesis. The high TSPO expression levels observed in microglia prompted us to assess its role in de novo neurosteroidogenesis. TSPO siRNA and TSPO synthetic ligand treatments were used to reduce and prompt TSPO function, respectively. The TSPO expression downregulation compromised the de novo neurosteroidogenesis and led to an increase in StAR expression, probably as a compensatory mechanism. The pharmacological TSPO stimulation the de novo neurosteroidogenesis improved in turn the neurosteroid-mediated release of Brain-Derived Neurotrophic Factor. In conclusion, these results demonstrated that de novo neurosteroidogenesis occurs in human microglia, unravelling a new mechanism potentially useful for future therapeutic purposes.https://www.mdpi.com/1422-0067/22/6/311518 kDa TSPOhuman microglial cellsneurosteroidogenesisneurosteroidsCYP11A1StAR protein |
| spellingShingle | Lorenzo Germelli Eleonora Da Pozzo Chiara Giacomelli Chiara Tremolanti Laura Marchetti Christian H. Wetzel Elisabetta Barresi Sabrina Taliani Federico Da Settimo Claudia Martini Barbara Costa De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein International Journal of Molecular Sciences 18 kDa TSPO human microglial cells neurosteroidogenesis neurosteroids CYP11A1 StAR protein |
| title | De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein |
| title_full | De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein |
| title_fullStr | De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein |
| title_full_unstemmed | De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein |
| title_short | De novo Neurosteroidogenesis in Human Microglia: Involvement of the 18 kDa Translocator Protein |
| title_sort | de novo neurosteroidogenesis in human microglia involvement of the 18 kda translocator protein |
| topic | 18 kDa TSPO human microglial cells neurosteroidogenesis neurosteroids CYP11A1 StAR protein |
| url | https://www.mdpi.com/1422-0067/22/6/3115 |
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