Galectin-3 initiates epithelial-stromal paracrine signaling to shape the proteolytic microenvironment during corneal repair.

Paracrine interactions between epithelial cells and stromal fibroblasts occur during tissue repair, development, and cancer. Crucial to these processes is the production of matrix metalloproteinases (MMPs) that modify the microenvironment. Here, we demonstrated that the carbohydrate-binding protein galectin-3 stimulated microenvironment remodeling in the cornea by promoting the paracrine action of secreted interleukin-1β (IL-1β). Through live cell imaging in vitro, we observed rapid activation of the MMP9 promoter in clusters of cultured human epithelial cells after direct heterotypic contact with single primary human fibroblasts. Soluble recombinant galectin-3 and endogenous galectin-3 of epithelial origin both stimulated MMP9 activity through the induction of IL-1β secretion by fibroblasts. In vivo, mechanical disruption of the basement membrane in wounded corneas prompted an increase in the abundance of IL-1β in the stroma and increased the amount of gelatinase activity in the epithelium. Moreover, corneas of galectin-3-deficient mice failed to stimulate IL-1β after wounding. This mechanism of paracrine control has broad importance for our understanding of how the proteolytic microenvironment is modified in epithelial-stromal interactions.