IL-17-driven induction of Paneth cell antimicrobial functions protects the host from microbiota dysbiosis and inflammation in the ileum

• DOI: 10.1016/j.mucimm.2023.01.005
• Publication Date: 2023-02-03T02:50:02Z
• Authors: Tomáš Brabec; Matouš Vobořil; Dagmar Schierová; Evgeny Valter; Iva Šplíchalová; Jan Dobeš; Jiří Březina; Martina Dobešová; Aigerim Aidarova; Martin Jakubec; Jasper Manning; Richard Blumberg; Ari Waisman; Michal Kolář; Jan Kubovčiak; Dagmar Šrůtková; Tomáš Hudcovic; Martin Schwarzer; Eva Froňková; Tereza Pinkasová; Petr Jabandžiev; Dominik Filipp
• Keywords: Inflammation; Paneth Cells; 0303 health sciences; Receptors, Interleukin-17; Microbiota; Interleukin-17; Ileitis; 3. Good health; Mice; 03 medical and health sciences; Ileum; Animals; Humans; Dysbiosis; Child; Antimicrobial Peptides

Interleukin (IL)-17 protects epithelial barriers by inducing the secretion of antimicrobial peptides. However, the effect of IL-17 on Paneth cells (PCs), the major producers of antimicrobial peptides in the small intestine, is unclear. Here, we show that the targeted ablation of the IL-17 receptor (IL-17R) in PCs disrupts their antimicrobial functions and decreases the frequency of ileal PCs. These changes become more pronounced after colonization with IL-17 inducing segmented filamentous bacteria. Mice with PCs that lack IL-17R show an increased inflammatory transcriptional profile in the ileum along with the severity of experimentally induced ileitis. These changes are associated with a decrease in the diversity of gut microbiota that induces a severe ileum pathology upon transfer to genetically susceptible mice, which can be prevented by the systemic administration of IL-17a/f in microbiota recipients. In an exploratory analysis of a small cohort of pediatric patients with Crohn's disease, we have found that a portion of these patients exhibits a low number of lysozyme-expressing ileal PCs and a high ileitis severity score, resembling the phenotype of mice with IL-17R-deficient PCs. Our study identifies IL-17R-dependent signaling in PCs as an important mechanism that maintains ileal homeostasis through the prevention of dysbiosis.