Interleukin-18 Constrains the Intestinal Tuft Cell-Driven Responses During Helminth Infection.

Authors

Mengyuan Dai, Zhiqiang Yan, Xinyu Lei, Jian Xue, Shan Yue, Mingying Zhang, Huihui Li, Yujuan Shen, Wei Xu

Published in

Immunology. Aug 01, 2026. Epub Aug 01, 2026.

Abstract

Type 2 immunity at mucosal surfaces is essential for helminth clearance, tissue repair, and barrier maintenance, processes governed by a robust feed-forward circuit between chemosensory tuft cells and group 2 innate lymphoid cells (ILC2s). However, the regulatory mechanisms that calibrate the magnitude and duration of this epithelial immune circuit remain incompletely defined. Here, we identify interleukin-18 (IL-18), a cytokine traditionally associated with type 1 immunity, as a key regulator of tuft cell-mediated type 2 responses during Nippostrongylus brasiliensis (N. brasiliensis) infection. IL-18-deficient (Il18^-/-) mice exhibited reduced intestinal worm burden at day 7 post-infection, which correlated with an expansion of tuft cell lineage, increased expression of tuft cell and type 2 response associated genes, and enhanced ILC2 responses. Consistent with these findings, loss of IL-18 receptor (Il18r1^-/-) further enhanced succinate-induced tuft cell hyperplasia. Within the intestinal epithelium, tuft cells were found to preferentially express IL-18Rα, suggesting potentially direct responsiveness to IL-18. Using small intestinal organoid models, we demonstrate that IL-18 directly attenuates IL-13-induced tuft cell differentiation, proliferation, and signature gene expression in an IL-18Rα-dependent manner. Mechanistically, pharmacological inhibition of p38 MAPK partially reversed the inhibitory effects of IL-18, identifying p38 signalling as a critical downstream mediator of this regulatory process. Together, these findings reveal that IL-18 functions as a negative feedback signal to constrain tuft cell-associated type 2 epithelial responses during helminth infection, thereby maintaining the balance between protective anti-helminth immunity and mucosal homeostasis.

PMID:
42538852
Bibliographic data and abstract were imported from PubMed on 01 Aug 2026.

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