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- Title
Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis.
- Authors
Wang, Ying; Han, Jing; Yang, Guang; Zheng, Shuhui; Zhou, Gaoshi; Liu, Xinjuan; Cao, Xiaocang; Li, Guang; Zhang, Bowen; Xie, Zhuo; Li, Li; Zhang, Mudan; Li, Xiaoling; Chen, Minhu; Zhang, Shenghong
- Abstract
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. The early stages of inflammatory bowel disease involve mucus injury and depletion of goblet cells. Here, the authors show that SPINK4 could serve as a serological biomarker of IBD and holds therapeutic potential for goblet cell regeneration via intrinsic EGFR activation under colitic conditions
- Subjects
INFLAMMATORY bowel diseases; COLITIS; PROTEASE inhibitors; INTESTINAL diseases; SERINE; KNOCKOUT mice
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-50048-y