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. RNA-seq of mouse colon lamina propria