Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis.

Autor: Wang Y; Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China., Han J; Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.; Division of Gastroenterology, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, P. R. China., Yang G; Department of Minimally Invasive Intervention, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China., Zheng S; Research Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China., Zhou G; Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China., Liu X; Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Chaoyang District, Beijing, P. R. China., Cao X; Department of Hepato-Gastroenterology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, P. R. China., Li G; Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Chaoyang District, Beijing, P. R. China., Zhang B; College of Life Sciences, Beijing Normal University, Beijing, P. R. China., Xie Z; Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China., Li L; Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China., Zhang M; Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China., Li X; Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China., Chen M; Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China., Zhang S; Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China. zhshh3@mail.sysu.edu.cn.; Division of Gastroenterology, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, P. R. China. zhshh3@mail.sysu.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 12; Vol. 15 (1), pp. 5874. Date of Electronic Publication: 2024 Jul 12.
DOI: 10.1038/s41467-024-50048-y
Abstrakt: Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type serine protease inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Notably, its therapeutic potential is synergistic with existing TNF-α inhibitor infliximab in colitis treatment. Mechanistically, SPINK4 promotes GC differentiation using a Kazal-like motif to modulate EGFR-Wnt/β-catenin and -Hippo pathways. Microbiota-derived diacylated lipoprotein Pam2CSK4 triggers SPINK4 production. We also show that monitoring SPINK4 in circulation is a reliable noninvasive technique to distinguish IBD patients from healthy controls and assess disease activity. Thus, SPINK4 serves as a serologic biomarker of IBD and has therapeutic potential for colitis via intrinsic EGFR activation in intestinal homeostasis.
(© 2024. The Author(s).)
Databáze: MEDLINE
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