Plasma-derived exosomes from Graves' orbitopathy: Pathogenic entities causing tissue lesions.

Area of Science:

• Immunology
• Ophthalmology
• Cell Biology

Background:

• Graves' orbitopathy (GO) is an autoimmune disorder causing orbital inflammation, fibrosis, and adipogenesis.
• Circulating exosomes are key intercellular communicators implicated in autoimmune diseases.
• The specific role of exosomes in GO pathogenesis and disease progression remains unclear.

Purpose of the Study:

• To investigate the pathogenic role of circulating exosomes in Graves' orbitopathy.
• To elucidate the mechanisms by which exosomes drive systemic-to-local disease progression in GO.
• To identify potential therapeutic targets within exosome-mediated pathways.

Main Methods:

• Isolated and characterized exosomes from GO patients (GO-Exos) and healthy controls.
• Assessed exosome effects on human orbital fibroblasts in vitro.
• Developed a murine model of GO using GO-Exos administration.
• Evaluated disease progression via clinical, histopathological, imaging, and single-cell RNA sequencing analyses.
• Investigated the role of miR-221-5p and the CACNG4/AMPK pathway.

Main Results:

• GO-Exos induced proinflammatory, profibrotic, and adipogenic phenotypes in orbital fibroblasts, upregulating IGF-1R and TSHR.
• In vivo administration of GO-Exos recapitulated GO hallmarks in mice, including thyroid dysfunction and orbital changes.
• miR-221-5p was identified as a key mediator of orbital remodeling by suppressing CACNG4/AMPK.
• Single-cell RNA sequencing revealed exosome-driven cellular reprogramming, including altered immune cell populations.

Conclusions:

• Circulating exosomes are novel pathogenic drivers in Graves' orbitopathy.
• Exosomes mediate immunopathogenesis in autoimmune orbitopathies through mechanisms like miR-221-5p.
• These findings provide a basis for understanding exosome-driven autoimmunity in GO and related conditions.