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

作者：Ying Wang, Jing Han, Guang Yang, Shuhui Zheng, Gaoshi Zhou, Xinjuan Liu, Xiaocang Cao, Guang Li, Bowen Zhang, Zhuo Xie, Li Li, Mudan Zhang, Xiaoling Li, Minhu Chen, Shenghong Zhang · 发表于：Nature Communications · 年份：2024 · DOI：10.1038/s41467-024-50048-y · 被引用次数：18 · 研究领域：Hippo pathway signaling and YAP/TAZ、Cell Adhesion Molecules Research、Immunotherapy and Immune Responses

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.