Yang Won Ho, Aziz Peter V, Heithoff Douglas M, Kim Yeolhoe, Ko Jeong Yeon, Cho Jin Won, Mahan Michael J, Sperandio Markus, Marth Jamey D
Sanford-Burnham-Prebys Medical Discovery Institute, Infectious and Inflammatory Diseases Center; La Jolla, CA 92037, USA.
Glycosylation Network Research Center and Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
iScience. 2023 Sep 9;26(10):107883. doi: 10.1016/j.isci.2023.107883. eCollection 2023 Oct 20.
The colonic mucosal barrier protects against infection, inflammation, and tissue ulceration. Composed primarily of Mucin-2, proteolytic erosion of this barrier is an invariant feature of colitis; however, the molecular mechanisms are not well understood. We have applied a recurrent food poisoning model of acquired inflammatory bowel disease using Typhimurium to investigate mucosal barrier erosion. Our findings reveal an innate Toll-like receptor 4-dependent mechanism activated by previous infection that induces Neu3 neuraminidase among colonic epithelial cells concurrent with increased Cathepsin-G protease secretion by Paneth cells. These anatomically separated host responses merge with the desialylation of nascent colonic Mucin-2 by Neu3 rendering the mucosal barrier susceptible to increased proteolytic breakdown by Cathepsin-G. Depletion of Cathepsin-G or Neu3 function using pharmacological inhibitors or genetic-null alleles protected against Mucin-2 proteolysis and barrier erosion and reduced the frequency and severity of colitis, revealing approaches to preserve and potentially restore the mucosal barrier.
结肠黏膜屏障可抵御感染、炎症和组织溃疡。该屏障主要由黏蛋白-2组成，其蛋白水解性侵蚀是结肠炎的一个不变特征；然而，其分子机制尚未完全明确。我们应用鼠伤寒沙门氏菌诱发的后天性炎症性肠病复发性食物中毒模型来研究黏膜屏障侵蚀。我们的研究结果揭示了一种由先前感染激活的先天性Toll样受体4依赖性机制，该机制可诱导结肠上皮细胞中的Neu3神经氨酸酶表达，同时潘氏细胞分泌的组织蛋白酶G蛋白酶增加。这些在解剖学上分离的宿主反应与Neu3对新生结肠黏蛋白-2的去唾液酸化作用相结合，使黏膜屏障易于受到组织蛋白酶G蛋白水解作用增强的影响。使用药理学抑制剂或基因敲除等位基因耗尽组织蛋白酶G或Neu3功能可防止黏蛋白-2蛋白水解和屏障侵蚀，并降低结肠炎的频率和严重程度，揭示了保护并可能恢复黏膜屏障的方法。
