869 IL-17 Promotes Human Primary Keratinocyte Invasion Potential by Controlling Cell Mechanics: A Novel MMP-independent Mechanobiology Pathway

The IL-17 secreting Th17 cells are one of the most predominant cells in the inflamed skin of inflammatory diseases like psoriasis as well as in skin carcinoma. IL-17 promotes migration of human primary keratinocytes (HPKs) by regulating extracellular matrix (ECM) remodelling via matrix metalloproteinase (MMPs) activity. However, the MMP-independent mechanisms of IL-17 mediated HPKs invasion potential have not been examined yet. With this study, we examined the role of IL-17 on cellular deformability and its impact on MMP-independent invasion potential of HPKs. IL17 increased the contractility of the HPKs by almost two-fold (p<0.001), as demonstrated by deadhesion assay. Further, increase in the contractility of IL17 treated HPKs was correlated with a reduction in the focal adhesion numbers as well as a reduction in cell spread area in a highly reproducible manner. Interestingly, IL-17 significantly increased the random motility of HPKs on two-dimensional (2D) surfaces. More importantly, IL-17 significantly increased the invasion of HPKs when cells were embedded in three-dimensional (3D) collagen matrix as well. Finally, blocking the cellular contractility by MLC kinases inhibitors significantly reduced the IL-17 mediated random migration and invasion in HPKs. In conclusion, our data delineate a novel MMP-independent pathway of IL-17 mediated HPKs migration and invasion in skin inflammatory diseases and in cancer.