Dectin-1 epigenetic reprogramming rescues senescent-like Treg function in allergic asthma

Area of Science:

• Immunology
• Cellular Biology
• Molecular Medicine

Background:

• Allergic asthma involves immune dysregulation and impaired regulatory T-cell (Treg) function.
• Mechanisms underlying Treg impairment and therapeutic correction are not fully understood.

Purpose of the Study:

• To investigate the mechanisms of Treg dysfunction in allergic asthma.
• To evaluate the therapeutic potential of KQS-1 in restoring Treg function and ameliorating asthma symptoms.

Main Methods:

• Analysis of Treg senescence markers (telomere length, SA-β-gal activity, apoptosis) in patients.
• Assessment of Treg suppressive capacity and cytokine profiles.
• Investigation of KQS-1 effects on Treg function, gene expression (FOXP3, IL-10), signaling pathways (Raf-1/ROS), and epigenetic modifications (H3K4me3, H3K27ac).
• Validation in mouse models of allergic asthma and adoptive transfer experiments.

Main Results:

• Patient Tregs exhibited senescence, reduced suppressive capacity, and a pro-inflammatory cytokine shift.
• KQS-1 treatment restored Treg suppressive function and anti-inflammatory cytokine production.
• Functional rescue was dependent on Dectin-1 binding and a Raf-1/ROS signaling axis, leading to epigenetic changes at FOXP3 and IL10 loci.
• CRISPR-mediated Dectin-1 deletion abolished KQS-1 effects.
• KQS-1 treatment attenuated airway hyperresponsiveness, inflammation, and remodeling in mouse models.

Conclusions:

• Treg senescence and dysfunction are key features of allergic asthma.
• KQS-1 effectively restores Treg function through Dectin-1, Raf-1/ROS signaling, and epigenetic remodeling.
• KQS-1 demonstrates therapeutic potential for allergic asthma by improving Treg function and reducing airway pathology.