Trem2/Tyrobp Signaling Protects Against Aortic Dissection and Rupture by Inhibiting Macrophage Activation in Mice

Area of Science:

• Cardiovascular Biology
• Immunology
• Molecular Biology

Background:

• Aortic dissection (AD) is closely linked to inflammation.
• The Trem2 (triggering receptor expressed on myeloid cells 2)/Tyrobp (TYRO protein tyrosine kinase-binding protein) pathway regulates innate immunity and is implicated in cardiovascular diseases, but its role in AD is unknown.

Purpose of the Study:

• To investigate the role of the Trem2/Tyrobp signaling pathway in the development and progression of aortic dissection.
• To identify potential therapeutic targets for AD based on this pathway.

Main Methods:

• Network analysis of human and mouse AD transcriptome data to identify hub genes.
• Generation and analysis of Tyrobp and Trem2 knockout mouse models of AD.
• Assessment of AD incidence, aortic wall pathology, and macrophage infiltration.
• Investigation of Toll-like receptor (TLR)-4 signaling and macrophage activation.

Main Results:

• Tyrobp was identified as a hub gene in AD, with elevated expression in human and mouse AD.
• Tyrobp deficiency significantly increased AD incidence, extracellular matrix degradation, and macrophage infiltration.
• Macrophage depletion and TLR4 inhibition mitigated the adverse effects of Tyrobp deficiency.
• Trem2 deficiency aggravated AD, while Trem2 agonist treatment provided protection.

Conclusions:

• The Trem2/Tyrobp axis plays a critical role in AD development.
• Targeting the Trem2/Tyrobp pathway presents a potential therapeutic strategy for AD.
• Further research is needed to confirm the role of Trem2/Tyrobp in human AD.