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

Autoři	BRABEC Tomas VOBOŘIL Matouš SCHIEROVA Dagmar VALTER Evgeny SPLICHALOVA Iva DOBEŠ Jan BREZINA Jiri DOBESOVA Martina AIDAROVA Aigerim JAKUBEC Martin MANNING Jasper BLUMBERG Richard WAISSMAN Ari KOLAR Michal KUBOVCIAK Jan SRUTKOVA Dagmar HUDCOVIC Tomas SCHWARZER Martin FRONKOVA Eva PINKASOVÁ Tereza JABANDŽIEV Petr FILIPP Dominik
Rok publikování	2023
Druh	Článek v odborném periodiku
Časopis / Zdroj	Mucosal Immunology
Fakulta / Pracoviště MU	Lékařská fakulta
Citace
www	https://www.sciencedirect.com/science/article/pii/S1933021923000053?via%3Dihub
Doi	http://dx.doi.org/10.1016/j.mucimm.2023.01.005
Klíčová slova	Paneth cells; IL-17 Signaling; Antimicrobial peptides; Crohn's disease; ileal microbiota
Popis	IL-17 protects epithelial barriers by inducing the secretion of antimicrobial peptides (AMPs). However, the effect of IL-17 on Paneth cells (PCs), the major producers of AMPs in the small intestine, is unclear. Here, we show that 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 (SFB). 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 exhibit 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.