Decreased lymph node estrogen levels cause nonremitting progressive experimental autoimmune encephalomyelitis disease

Area of Science:

• Immunology
• Endocrinology
• Neuroscience

Background:

• Estrogen modulates immune responses and is crucial in multiple sclerosis (MS).
• Aromatase is the enzyme responsible for estrogen synthesis.
• Lymph nodes (LNs) are key sites for immune cell interaction and regulation.

Purpose of the Study:

• To investigate aromatase expression and estrogen synthesis in LNs.
• To determine the role of LN-derived estrogen in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a model for MS.
• To explore the impact of aging on estrogen synthesis in LNs and its relation to MS.

Main Methods:

• Utilized Cyp19-RFP reporter mice to visualize aromatase-expressing cells in LNs.
• Quantified 17β-estradiol synthesis in LNs.
• Administered an aromatase inhibitor directly to LNs in an EAE mouse model.
• Assessed EAE phenotype and spinal cord gray matter atrophy.

Main Results:

• Aromatase activity was detected in high endothelial venules of LNs, confirming local estrogen synthesis.
• LN estrogen synthesis declined with age.
• Inhibition of LN aromatase led to an interferon-β-resistant EAE phenotype with significant gray matter atrophy.
• Aromatase expression was also observed in human cervical LNs.

Conclusions:

• Lymph nodes are significant sites of de novo 17β-estradiol production.
• Reduced estrogen synthesis in aging LNs may exacerbate MS pathogenesis.
• Targeting LN estrogen synthesis offers a potential therapeutic strategy for MS.