Interepithelial inflammatory crosstalk mediated by stromal fibroblast communication through hyaluronan [dataset 2]

Inflammation of epithelial structures frequently leads to disease at distal organs, but the mechanism responsible for this is unknown. We report evidence that digestion of hyaluronan in the extracellular matrix signals distal stromal cells to become primed for increased inflammation. By applying transgenic mouse models and single cell RNA sequencing of mouse and human tissues we demonstrate that skin injury or infection promotes an adipogenic response in distinct populations of distant submucosal fibroblasts of the colon. This response can be recapitulated without skin inflammation by expression of hyaluronidase in skin that promotes a highly amplified and frequently fatal host response to intestinal injury. Our results uncover an innate system of communication between epithelial stroma that is not initiated by immunocyte trafficking or cytokine signaling. Overall design: RNA-seq of mouse colon lamina propria

上皮结构的炎症常可引发远端器官病变，但其具体致病机制迄今尚未阐明。本研究报道了一项关键发现：细胞外基质中的透明质酸（hyaluronan）被降解后，可向远端基质细胞传递信号，使其致敏以增强炎症应答。我们通过构建转基因小鼠模型，并对小鼠与人类组织开展单细胞RNA测序（single cell RNA sequencing）实验，证实皮肤损伤或感染可诱导结肠远端黏膜下层的特定成纤维细胞亚群产生成脂分化反应。该成脂反应可在无皮肤炎症的情况下，通过在皮肤组织中表达透明质酸酶（hyaluronidase）得以复现；而该操作会促使宿主对肠道损伤产生高度放大、且常可致命的应答反应。本研究结果揭示了一套全新的上皮基质间先天通信系统，该系统并非由免疫细胞迁移或细胞因子信号所启动。整体实验设计：小鼠结肠固有层RNA-seq