Fibroblast-Mediated MMP2 Contribution to Nonresponse in Anti-TNFα Therapy for Crohn’s Disease

作者：Danshu Wang, Dehao Zhu, Xiangyu Zhao, Jiaxin Wang, Haiming Zhuang, Yao Zhang, Duowu Zou · 发表于：Inflammatory Bowel Diseases · 年份：2025 · DOI：10.1093/ibd/izaf263 · 被引用次数：1 · 研究领域：Inflammatory Bowel Disease、Protease and Inhibitor Mechanisms、Peptidase Inhibition and Analysis

BACKGROUND: Despite the transformative impact of biologics on the treatment of inflammatory bowel disease (IBD) in recent years, a substantial proportion of patients remain unresponsive to these advanced therapies. Overcoming resistance remains a significant clinical challenge, largely due to the incomplete understanding of its underlying mechanisms. This study explores the role of extracellular matrix (ECM) remodeling in the development of resistance to anti-TNFα therapy. METHODS: Using public single-cell and bulk transcriptomic datasets, combined with in vitro primary cell experiments and multiplex immunofluorescence validation, we investigated key factors contributing to therapy failure. RESULTS: Transcriptomic analysis revealed that ECM-related pathways were enriched in Crohn's disease patients and associated with resistance to anti-TNFα therapy. Single-cell analysis identified Fibroblast 2 (CD81+ fibroblasts) as the major ECM-related stromal subpopulation, exhibiting the highest capacity for ECM secretion and degradation. Matrix metalloproteinase-2 (MMP2) was identified as a key protease highly expressed in this subset, showing close interaction with macrophages. Co-culture of primary fibroblasts and macrophages led to increased release of inflammatory mediators such as TNFα and IL-6, which was partially reduced by MMP2 inhibition, suggesting a potential regulatory role of MMP2 in fibroblast-macrophage crosstalk. Spatial transcriptomics and multiplex immunofluorescence f...