Tuft cells trigger neurogenic inflammation in the urethra.

Cholinergic urethral tuft cells (UTCs) are regarded as sentinels of microbial products in the urogenital tract, initiating reflex micturition as a protective mechanism. We here hypothesize that acetylcholine released by stimulated UTC leads to neurogenic inflammation by triggering neuropeptide (substance P and calcitonin gene-related peptide) release from nearby sensory nerve terminals. In the mouse urethra, we find that peptidergic nerve fibers expressing a nicotinic acetylcholine receptor are in contact with UTC. Optogenetic activation of UTC and the UTC activator denatonium leads to the release of neuropeptides from explanted urethrae through cholinergic nicotinic signaling. In vivo, intraurethral application of denatonium induces plasma extravasation, a hallmark of neurogenic inflammation, which is sensitive to genetic interruption of the UTC intracellular signaling cascade (Trpm5-/-) and blockade of the substance P receptor: neurokinin-1 receptor. Thus, UTCs not only trigger long-distance reflexes involving the bladder but also evoke neurogenic inflammation, representing a local defense reaction.