Interplay between androgen and CXCR4 chemokine signaling in myelin repair
Abstract In men, reduced levels of testosterone are associated with the prevalence and progression of multiple sclerosis (MS), a chronic and disabling demyelinating disorder. Testosterone has been shown to promote myelin repair. Here, we demonstrate that the cooperation between testosterone and CXCR...
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-024-01730-1 |
| _version_ | 1797272809664151552 |
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| author | Narimène Asbelaoui Charly Abi-Ghanem Géraldine Schlecht-Louf Hania Oukil The Netherlands Brain Bank Michael Schumacher Abdel Mouman Ghoumari |
| author_facet | Narimène Asbelaoui Charly Abi-Ghanem Géraldine Schlecht-Louf Hania Oukil The Netherlands Brain Bank Michael Schumacher Abdel Mouman Ghoumari |
| author_sort | Narimène Asbelaoui |
| collection | DOAJ |
| description | Abstract In men, reduced levels of testosterone are associated with the prevalence and progression of multiple sclerosis (MS), a chronic and disabling demyelinating disorder. Testosterone has been shown to promote myelin repair. Here, we demonstrate that the cooperation between testosterone and CXCR4 signaling involving astrocytes is required for myelin regeneration after focal demyelination produced in the ventral mouse spinal cord by the infusion of lysolecithin. The testosterone-dependent remyelination of axons by oligodendrocytes was accompanied by an increase in astrocytes expressing CXCR4, its ligand CXCL12 and the androgen receptor (AR) within the demyelinated area. Depriving males of their testosterone or pharmacological inhibition of CXCR4, with the selective antagonist AMD3100, prevented the appearance of astrocytes expressing CXCR4, CXCL12 and AR within the demyelinated area and the concomitant recruitment of myelin forming oligodendrocytes. Conditional genetic ablation of either CXCR4 or AR in astrocytes also completely blocked the formation of new myelin by oligodendrocytes. Interestingly, the gain of function mutation in CXCR4 causing WHIM syndrome allows remyelination to take place, even in the absence of testosterone, but its potentiating effects remained observable. After testosterone deprivation or CXCR4 inhibition, the absence of astrocytes within the demyelinated area led to the incursion of Schwann cells, most likely derived from spinal nerves, and the formation of peripheral nerve type myelin. In patients with progressive MS, astrocytes expressing CXCR4 and AR surrounded myelin lesions, and their presence opposed the incursion of Schwann cells. These results highlight a mechanism of promyelinating testosterone signaling and the importance of normalizing its levels in combined myelin repair therapies. |
| first_indexed | 2024-03-07T14:35:41Z |
| format | Article |
| id | doaj.art-31f51b5ad97d44a495a82252831844e3 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-07T14:35:41Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-31f51b5ad97d44a495a82252831844e32024-03-05T20:40:38ZengBMCActa Neuropathologica Communications2051-59602024-01-0112112510.1186/s40478-024-01730-1Interplay between androgen and CXCR4 chemokine signaling in myelin repairNarimène Asbelaoui0Charly Abi-Ghanem1Géraldine Schlecht-Louf2Hania Oukil3The Netherlands Brain Bank4Michael Schumacher5Abdel Mouman Ghoumari6UMR1195, “Diseases and Hormones of the Nervous System”, Inserm and University Paris-SaclayUMR1195, “Diseases and Hormones of the Nervous System”, Inserm and University Paris-SaclayINSERM UMR 996, Inserm, Inflammation, Microbiome and Immunosurveillance, Faculté de Pharmacie, Université Paris-SaclayUMR1195, “Diseases and Hormones of the Nervous System”, Inserm and University Paris-SaclayNetherlands Institute for NeuroscienceUMR1195, “Diseases and Hormones of the Nervous System”, Inserm and University Paris-SaclayUMR1195, “Diseases and Hormones of the Nervous System”, Inserm and University Paris-SaclayAbstract In men, reduced levels of testosterone are associated with the prevalence and progression of multiple sclerosis (MS), a chronic and disabling demyelinating disorder. Testosterone has been shown to promote myelin repair. Here, we demonstrate that the cooperation between testosterone and CXCR4 signaling involving astrocytes is required for myelin regeneration after focal demyelination produced in the ventral mouse spinal cord by the infusion of lysolecithin. The testosterone-dependent remyelination of axons by oligodendrocytes was accompanied by an increase in astrocytes expressing CXCR4, its ligand CXCL12 and the androgen receptor (AR) within the demyelinated area. Depriving males of their testosterone or pharmacological inhibition of CXCR4, with the selective antagonist AMD3100, prevented the appearance of astrocytes expressing CXCR4, CXCL12 and AR within the demyelinated area and the concomitant recruitment of myelin forming oligodendrocytes. Conditional genetic ablation of either CXCR4 or AR in astrocytes also completely blocked the formation of new myelin by oligodendrocytes. Interestingly, the gain of function mutation in CXCR4 causing WHIM syndrome allows remyelination to take place, even in the absence of testosterone, but its potentiating effects remained observable. After testosterone deprivation or CXCR4 inhibition, the absence of astrocytes within the demyelinated area led to the incursion of Schwann cells, most likely derived from spinal nerves, and the formation of peripheral nerve type myelin. In patients with progressive MS, astrocytes expressing CXCR4 and AR surrounded myelin lesions, and their presence opposed the incursion of Schwann cells. These results highlight a mechanism of promyelinating testosterone signaling and the importance of normalizing its levels in combined myelin repair therapies.https://doi.org/10.1186/s40478-024-01730-1RemyelinationAndrogen receptorTestosteroneChemokine receptorAstrocytesSchwann cells |
| spellingShingle | Narimène Asbelaoui Charly Abi-Ghanem Géraldine Schlecht-Louf Hania Oukil The Netherlands Brain Bank Michael Schumacher Abdel Mouman Ghoumari Interplay between androgen and CXCR4 chemokine signaling in myelin repair Acta Neuropathologica Communications Remyelination Androgen receptor Testosterone Chemokine receptor Astrocytes Schwann cells |
| title | Interplay between androgen and CXCR4 chemokine signaling in myelin repair |
| title_full | Interplay between androgen and CXCR4 chemokine signaling in myelin repair |
| title_fullStr | Interplay between androgen and CXCR4 chemokine signaling in myelin repair |
| title_full_unstemmed | Interplay between androgen and CXCR4 chemokine signaling in myelin repair |
| title_short | Interplay between androgen and CXCR4 chemokine signaling in myelin repair |
| title_sort | interplay between androgen and cxcr4 chemokine signaling in myelin repair |
| topic | Remyelination Androgen receptor Testosterone Chemokine receptor Astrocytes Schwann cells |
| url | https://doi.org/10.1186/s40478-024-01730-1 |
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