Targeting epithelial cell-derived TWIST1 alleviates allergic asthma

Area of Science:

• Immunology
• Molecular Biology
• Respiratory Medicine

Background:

• T Helper 2 (Th2) cell bias is crucial in allergic asthma pathogenesis.
• The mechanisms maintaining Th2 bias in local airway tissues are not fully understood.
• Interleukin-33 (IL-33) is essential for Th2 polarization, and TWIST1 regulates cellular functions, while aberrant RAS activation sustains cellular activities.

Purpose of the Study:

• To investigate the role of TWIST1 and RAS activation interaction in inducing and maintaining Th2 polarization in allergic asthma.
• To explore the association between TWIST1, RAS, and IL-33 expression in airway epithelial cells (AECs) of asthma patients.

Main Methods:

• Isolation of airway epithelial cells (AECs) from broncho-alveolar lavage fluids of asthma patients.
• RNA sequencing to identify mediators involved in IL-33 over-expression.
• Establishment of a mouse model to assess the roles of TWIST1 and RAS in allergic asthma development.

Main Results:

• Strong TWIST1 expression in asthma patients correlated positively with asthmatic responses.
• TWIST1 promoted IL-33 expression in AECs, and Twist1-deficient AEC-carrying mice failed to induce Th2 polarization.
• TWIST1 expression in AECs was positively associated with RAS activation in asthma patients.
• The interaction between RAS and TWIST1 in AECs sustained airway allergic inflammation.
• Inhibition of TWIST1 or RAS prevented experimental asthma-like inflammation in mice.

Conclusions:

• The interaction between TWIST1 and RAS induces and maintains IL-33 expression in AECs, facilitating allergic airway inflammation.
• Targeting the TWIST1-RAS interaction offers a potential therapeutic strategy for allergic asthma.