Golob Jonathan L, Hou Guoqing, Swanson Benjamin J, Berinstein Jeffrey A, Bishu Shreenath, Grasberger Helmut, Zataari Mohamed El, Lee Allen, Kao John Y, Kamada Nobuhiko, Bishu Shrinivas
Division of Infectious Diseases, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Division of Gastroenterology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
Inflamm Bowel Dis. 2025 Apr 10;31(4):1082-1094. doi: 10.1093/ibd/izae293.
Inflammation can generate pathogenic Th17 cells and cause an inflammatory dysbiosis. In the context of inflammatory bowel disease (IBD), these inflammatory Th17 cells and dysbiotic microbiota may perpetuate injury to intestinal epithelial cells. However, many models of IBD like T-cell transfer colitis and IL-10-/- mice rely on the absence of regulatory pathways, so it is difficult to tell if inflammation can also induce protective Th17 cells.
We subjected C57BL6, RAG1-/-, or JH-/- mice to systemic or gastrointestinal (GI) Citrobacter rodentium (Cr). Mice were then subjected to 2.5% dextran sodium sulfate (DSS) to cause epithelial injury. Fecal microbiota transfer was performed by bedding transfer and co-housing. Flow cytometry, qPCR, and histology were used to assess mucosal and systemic immune responses, cytokines, and tissue inflammation. 16s sequencing was used to assess gut bacterial taxonomy.
Transient inflammation with GI but not systemic Cr was protective against subsequent intestinal injury. This was replicated with sequential DSS collectively indicating that transient inflammation provides tissue-specific protection. Inflammatory Th17 cells that have a tissue-resident memory (TRM) signature expanded in the intestine. Experiments with reconstituted RAG1-/-, JH-/- mice, and cell trafficking inhibitors showed that inflammation-induced Th17 cells were required for protection. Fecal microbiota transfer showed that the inflammation-trained microbiota was necessary for protection, likely by maintaining protective Th17 cells in situ.
Inflammation can generate protective Th17 cells that synergize with the inflammation-trained microbiota to provide host resiliency against subsequent injury, indicating that inflammation-induced Th17 TRM T cells are heterogenous and contain protective subsets.
炎症可产生致病性Th17细胞并导致炎症性生态失调。在炎症性肠病（IBD）的背景下，这些炎症性Th17细胞和生态失调的微生物群可能会使肠道上皮细胞持续受损。然而，许多IBD模型，如T细胞转移结肠炎和IL-10基因敲除小鼠，依赖于缺乏调节途径，因此很难判断炎症是否也能诱导保护性Th17细胞。
我们将C57BL6、RAG1基因敲除或JH基因敲除小鼠暴露于全身性或胃肠道（GI）鼠柠檬酸杆菌（Cr）。然后给小鼠施用2.5%的葡聚糖硫酸钠（DSS）以引起上皮损伤。通过垫料转移和同笼饲养进行粪便微生物群移植。使用流式细胞术、qPCR和组织学来评估黏膜和全身免疫反应、细胞因子和组织炎症。使用16s测序来评估肠道细菌分类学。
胃肠道而非全身性Cr引起的短暂炎症对随后的肠道损伤具有保护作用。连续使用DSS可重复这一结果，总体表明短暂炎症提供了组织特异性保护。具有组织驻留记忆（TRM）特征的炎症性Th17细胞在肠道中扩增。对重组RAG1基因敲除、JH基因敲除小鼠和细胞转运抑制剂进行的实验表明，炎症诱导的Th17细胞是保护所必需的。粪便微生物群移植表明，经过炎症训练的微生物群对于保护是必要的，可能是通过在原位维持保护性Th17细胞来实现的。
炎症可产生保护性Th17细胞，这些细胞与经过炎症训练的微生物群协同作用，为宿主提供抵抗后续损伤的恢复力，这表明炎症诱导的Th17 TRM T细胞是异质性的，并且包含保护性亚群。
