PDF(Pubmed)
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.
摘要：
与杯状细胞（GC）消耗相关的粘液损伤构成了炎症性肠病（IBD）的早期事件。使用单细胞测序来检测粘液功能障碍中的关键事件，我们发现，Kazal型丝氨酸蛋白酶抑制剂SPINK4在结肠肠中与疾病活动并行受到动态调节。在化学诱导的结肠炎条件下，重组鼠SPINK4成功挽救了Spink4条件性基因敲除小鼠的严峻状态。值得注意的是,其治疗潜力与现有TNF-α抑制剂英夫利昔单抗在结肠炎治疗中具有协同作用.机械上,SPINK4使用Kazal样基序调节EGFR-Wnt/β-连环蛋白和-Hippo途径促进GC分化。微生物群衍生的二酰化脂蛋白Pam2CSK4触发SPINK4生产。我们还表明，监测循环中的SPINK4是一种可靠的非侵入性技术，可以区分IBD患者与健康对照并评估疾病活动。因此，SPINK4可作为IBD的血清学生物标志物，并通过肠道稳态中的内在EGFR激活具有治疗结肠炎的潜力。
