Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination

• Published in: Nature communications 2023-03, Vol.14 (1), p.1592-1592, Article 1592
• Main Authors: Zahaf, Amina, Kassoussi, Abdelmoumen, Hutteau-Hamel, Tom, Mellouk, Amine, Marie, Corentine, Zoupi, Lida, Tsouki, Foteini, Mattern, Claudia, Bobé, Pierre, Schumacher, Michael, Williams, Anna, Parras, Carlos, Traiffort, Elisabeth
• Format: Article
• Language: English
• Subjects: 13; 13/21; 13/31; 13/51; 38; 38/32; 38/91; 631/378/1687/1825; 631/378/1689/1666; 64; 64/60; 692/617/375/1411/1666; Androgen receptors; Androgens; Animal models; Animals; Autoimmune diseases; Catabolism; Demyelinating diseases; Demyelination; Disease Models, Animal; Estrogens; Female; Females; Genes; Humanities and Social Sciences; Immune system; Inflammation; Lesions; Life Sciences; Lipid metabolism; Lipids; Male; Males; Men; Mice; Microglia; multidisciplinary; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - pathology; Myelin; Myelin Sheath - physiology; Myelination; Neurons - pathology; Neurons and Cognition; Neuroprotection; Regeneration; Science; Science (multidisciplinary); Sex; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36846-w

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. Androgen effects have been poorly studied in demyelinating diseases in females. Here, authors show androgen requirement for proper myelin regeneration in females and the critical need to consider male-female differences in multiple sclerosis patients.