The role of keratinocyte alpha v beta6 integrin in the regulation of transforming growth factor beta during wound healing

The stratified squamous epithelium of skin and mucosa is mostly formed from keratinocytes and protects the organism from its surrounding environment. Any damage to this protective layer is restored through re-epithelialization – an essential part of wound healing. Therefore, studying the regulatory mechanisms of keratinocytes during re-epithelialization is important in understanding the processes involved in both normal and impaired wound healing. The keratinocyte αvβ6 integrin is induced during wound healing. Interestingly, αvβ6 integrin can activate both fibrogenic transforming growth factor-β1 (TGF-β1) and anti-fibrogenic TGF-β3. The role of αvβ6 integrin, however, especially in regards to the regulation of TGF-βs, during wound healing, is largely unknown. In the present study, we investigated the potential for the αvβ6 integrin-mediated regulation of TGF-β1 and TGF-β3 during wound healing in gingival and skin wound tissue sections. Furthermore, we investigated the possible regulatory mechanisms of TGF-β1 activity by αvβ6 integrin in keratinocytes. Spatio-temporal co-accumulation of αvβ6 integrin with TGF-β1 and TGF-β3 in the wound epithelium suggested that αvβ6 integrin may locally regulate both isoforms during wound healing. Prolonged co-expression of αvβ6 integrin and TGF-β3 in the scar-free gingival wound epithelium may potentially have an important role in the protection of gingiva from scarring. Our in vitro data showed that keratinocytes responded differentially to low levels of endogenously produced TGF-β1 compared to high amount of extracellular matrix (ECM)-bound latent TGF-β1. While the data were suggestive of activating endogenous TGF-β1 by the keratinocyte αvβ6 integrin, high levels of ECM-associated TGF-β1 was removed by keratinocytes in the presence of αvβ6 integrin allowing them to overcome the TGF-β1-mediated inhibitory effects on the cell proliferation. Taken together, our data showed a potential for the αvβ6 integrin-mediated local regulation of TGF-β1 and -β3 during wound healing. Prolonged expression and co-accumulation of αvβ6 integrin and TGF-β3 may be important in the protection of gingival wounds from scar formation. Our finding of αvβ6 integrin-mediated removal of the matrix-bound TGF-β1 in keratinocytes may be important at the time of wound closure, when keratinocytes typically show increased proliferation rate despite high levels of TGF-β1 in the surrounding matrix.Dentistry, Faculty ofGraduat