Beyond Epithelial to Mesenchymal Transition: A Novel Role for the Transcription Factor Snail in Inflammation and Wound Healing

Snail, a transcription factor linked to epithelial to mesenchymal transition (EMT) during embryonic development and tumor progression, is associated with migration of cells. During inflammation and tissue injury, cell movement is also observed to provide the first line of defense against bacteria and to promote wound healing. Therefore, we studied the function of Snail in activated macrophages in a variety of inflammatory processes. In this study, we examined the expression and localization of Snail during inflammation and tissue injury in rats and human tissue specimens, by immunohistochemistry, Western blot, and real-time PCR. We investigated Snail expression after stimulation of macrophages with TGF-beta 1, LPS, Interleukin-8, and MMP-3 in vitro. To further understand the role of Snail in activated macrophages, we used Stealth siRNA against Snail, transfected the human macrophage cell line THP-1, and measured migration of cells in an in vitro invasion assay. We found a strong, transient, and time-dependent activation of Snail in migrating macrophages at the sites of injury in vivo and in vitro, as well as in patients with inflammatory bowel disease. Furthermore, we showed that induction of Snail in macrophages is dependent on TGF-beta 1 signaling pathway. Downregulation of Snail by Stealth siRNA led to impaired migration of THP-1 cells in an invasion assay after stimulation with TGF-beta 1. We conclude that TGF-beta 1 induced migration of activated macrophages during inflammation and wound healing is mediated by snail. These results give insights in a novel EMT-like mechanism present in immune cell movement during tissue injury.