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. 2024 Jun 11;57(6):1243-1259.e8.
doi: 10.1016/j.immuni.2024.03.023. Epub 2024 May 13.

Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance

Tyler E Billipp  1 , Connie Fung  2 , Lily M Webeck  1 , Derek B Sargent  1 , Matthew B Gologorsky  3 , Zuojia Chen  4 , Margaret M McDaniel  1 , Darshan N Kasal  1 , John W McGinty  1 , Kaitlyn A Barrow  5 , Lucille M Rich  5 , Alessio Barilli  6 , Mark Sabat  7 , Jason S Debley  8 , Chuan Wu  4 , Richard Myers  7 , Michael R Howitt  3 , Jakob von Moltke  9
Affiliations

Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance

Tyler E Billipp et al. Immunity. .

Abstract

Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the "weep" response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine. This response required tuft cell sensory functions and tuft cell-derived acetylcholine (ACh), which acted directly on neighboring epithelial cells to stimulate chloride secretion, independent of neurons. Maximal tuft cell-induced chloride secretion coincided with immune restriction of helminths, and clearance was delayed in mice lacking tuft cell-derived ACh, despite normal type 2 inflammation. Thus, we have uncovered an epithelium-intrinsic response unit that uses ACh to couple tuft cell sensing to the secretory defenses of neighboring epithelial cells.

Keywords: acetylcholine; chloride secretion; helminth infection; intestine; tuft cell; type 2 immunity.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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