CD11c⁺CD69⁺ trained APCs in lungs mediate allergic asthma through increased H3K27ac

Area of Science:

• Immunology
• Epigenetics
• Respiratory Medicine

Background:

• Asthma is a chronic respiratory disease characterized by airway inflammation.
• Antigen-presenting cells (APCs) are critical immune cells involved in initiating and shaping adaptive immune responses.
• Trained immunity, a concept typically associated with innate immune cells, is increasingly recognized for its potential role in chronic inflammatory diseases like asthma.

Purpose of the Study:

• To investigate the role and underlying mechanisms of trained APCs in a mouse model of allergic asthma.
• To identify potential therapeutic targets for asthma based on the function of trained APCs.

Main Methods:

• Ovalbumin (OVA)-sensitized BALB/c, C57BL/6 J, and TNF-α knockout mice were used.
• CD11c+CD69+ APCs were isolated and characterized for trained immunity markers and function.
• Histone acetylation, epigenetic inhibitors, and TNF-α were assessed in vitro and in vivo.
• Adoptive transfer experiments were performed to evaluate the functional capacity of trained APCs.

Main Results:

• OVA sensitization induced CD11c+CD69+ trained APCs exhibiting enhanced responses and metabolic reprogramming (increased acetylcarnitine).
• These trained APCs displayed high H3K27ac levels, crucial for CD69 expression and development, and promoted Th2-type immune responses.
• Inhibition of histone acetyltransferase or TNF-α attenuated asthma development.
• Adoptive transfer of trained APCs induced asthma, which was dependent on TNF-α.

Conclusions:

• CD11c+CD69+ trained APCs are critical mediators of asthma pathogenesis.
• Histone acetylation and TNF-α are essential for the development and function of trained APCs in asthma.
• Targeting trained APCs, histone acetylation, or TNF-α presents a promising therapeutic strategy for asthma.