A succinate/SUCNR1-brush cell defense program in the tracheal epithelium

Area of Science:

• Immunology
• Cell Biology
• Respiratory Medicine

Background:

• Bacterial infections lead to succinate buildup in the airways.
• Succinate is a host-derived metabolite implicated in inflammatory responses.

Purpose of the Study:

• To elucidate the mechanism by which luminal succinate activates airway epithelial cells.
• To identify the signaling pathways involved in the epithelial response to succinate.
• To understand how this response contributes to airway innate immunity.

Main Methods:

• Murine tracheal brush (tuft) cell activation assays.
• Analysis of signaling cascades including succinate receptor 1 (SUCNR1), phospholipase Cβ2, and TRPM5.
• Calcium imaging to track wave propagation across the tracheal epithelium.
• Assessment of ciliary activity and chloride secretion.

Main Results:

• Luminal succinate activates tuft cells via SUCNR1, PLCβ2, and TRPM5.
• Activated tuft cells release acetylcholine, initiating a long-range Ca2+ wave.
• The Ca2+ wave propagates via muscarinic and gap junction signaling to ciliated and secretory cells.
• This coordinated response enhances ciliary beating and chloride secretion, boosting mucociliary clearance.

Conclusions:

• Tracheal brush cells act as a critical sensor for host-derived succinate.
• Succinate-induced signaling in brush cells triggers a global epithelial defense program.
• Enhanced mucociliary clearance is a key outcome of this innate airway defense mechanism.