Therapeutically targetable Th17-derived miR-721 drives autoimmune myocarditis through PPARγ repression

Area of Science:

• Immunology
• Cardiovascular Biology
• Molecular Biology

Background:

• Myocarditis involves Th17 immune responses contributing to heart failure.
• Current myocarditis therapies lack specificity.
• The role of miR-721 in myocarditis pathogenesis is largely unknown.

Purpose of the Study:

• To investigate the role of miR-721 in experimental autoimmune myocarditis (EAM) and human myocarditis.
• To elucidate the mechanism by which miR-721 influences Th17 cell responses.
• To evaluate miR-721 as a potential therapeutic target for myocarditis.

Main Methods:

• Characterization of miR-721 and its human homolog in extracellular vesicles (EVs) from Th17 cells of EAM mice and myocarditis patients.
• Validation of miR-721 target genes using luciferase reporter assays and knockout mice.
• In vivo functional studies involving miR-721 overexpression, inhibition, and blockade in EAM mice.
• Assessment of Th17 responses, cardiac inflammation, and cardiac function.

Main Results:

• miR-721 and its human homolog are secreted by Th17 cells in EVs during myocarditis.
• miR-721 promotes Th17 differentiation by repressing PPARγ (Peroxisome proliferator-activated receptor gamma).
• In vivo blockade of miR-721 reduced Th17 responses, cardiac inflammation, and improved cardiac function in EAM mice.

Conclusions:

• miR-721 is released by Th17 cells and drives myocarditis progression by suppressing PPARγ.
• miR-721 represents a novel mechanistic driver of myocarditis.
• Targeting miR-721 offers a potential therapeutic strategy for myocarditis.