Tuft cells trigger neurogenic inflammation in the urethra

Area of Science:

• Urology
• Neuroscience
• Immunology

Background:

• Cholinergic urethral tuft cells (UTCs) detect microbial products in the urogenital tract.
• UTCs initiate reflex micturition as a protective mechanism.
• The role of UTCs in local inflammatory responses is not well understood.

Purpose of the Study:

• To investigate the hypothesis that acetylcholine released by UTCs triggers neurogenic inflammation.
• To explore the mechanism involving neuropeptide release from sensory nerve terminals.

Main Methods:

• Optogenetic activation of UTCs and chemical stimulation with denatonium.
• Measurement of neuropeptide release from explanted urethrae.
• In vivo assessment of plasma extravasation following intraurethral denatonium application.
• Utilizing Trpm5 knockout mice and substance P receptor (neurokinin-1 receptor) blockade.

Main Results:

• Peptidergic nerve fibers expressing nicotinic acetylcholine receptors were found in contact with UTCs in the mouse urethra.
• UTC activation led to neuropeptide release via cholinergic nicotinic signaling.
• Intraurethral denatonium induced plasma extravasation, a marker of neurogenic inflammation.
• This inflammation was dependent on the UTC intracellular signaling cascade (Trpm5) and substance P receptor signaling.

Conclusions:

• UTCs not only trigger long-distance reflexes but also mediate local neurogenic inflammation.
• This represents a novel local defense reaction in the urogenital tract.
• UTCs play a dual role in both reflex micturition and local inflammatory responses.