TY - JOUR
T1 - Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination
AU - Zahaf, Amina
AU - Kassoussi, Abdelmoumen
AU - Hutteau-Hamel, Tom
AU - Mellouk, Amine
AU - Marie, Corentine
AU - Zoupi, Lida
AU - Tsouki, Fenia
AU - Mattern, Claudia
AU - Bobé, Pierre
AU - Schumacher, Michael
AU - Williams, Anna C
AU - Parras, Carlos
AU - Traiffort, Elisabeth
N1 - Funding Information:
This work was supported by the French Multiple Sclerosis Foundation ARSEP [RAK17128LLA; RAK19176LLA; RAK21128LLA to E.T.]. A.Z. was funded by Mattern Foundation. A.K. was funded by grants from the French Government and ARSEP. A.W., L.Z. and F.T. were funded by the MS Society UK. We thank UMS44 (Le Kremlin-Bicêtre), A. Schmidt and Imaging platform (Hôpital Cochin, Paris), Y. Marie and Genotyping/Sequencing core facility (ICM, Paris), D. Langui, A. Baskaran and ICM Quant platform (ICM, Paris) for technical assistance, ICM plateforms iSeq and DAC, particularly F-X. Lejeune for help in transcriptome normalization using housekeeping genes and C. Raoux for help in bulk RNA-seq deconvolution.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/3/22
Y1 - 2023/3/22
N2 - Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences.
AB - Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences.
U2 - 10.1038/s41467-023-36846-w
DO - 10.1038/s41467-023-36846-w
M3 - Article
C2 - 36949062
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
M1 - 1592
ER -