Podoplanin suppresses the cell adhesion of epidermal keratinocytes via functional regulation of 1-integrin

Epidermal stem cells adhere more efficiently to the extracellular matrix (ECM) than the less adhesive differentiating cells due to their high expression of cell adhesion molecules including 1-integrin. Podoplanin is majorly expressed in the markedly proliferative and differentiating basal cells of the wounded and psoriatic epidermis. This study was designed to reveal podoplanin's function in human epidermal keratinocytes (HEK) focusing on its interaction with 1-integrin. We analyzed the adhesion and differentiation of HEK in both podoplanin-overexpressing and -knock-down cells, considering their 1-integrin levels. The basal layer of IL-22-treated hyperproliferative reconstituted epidermis cells (simulating basal hyperproliferative psoriatic epidermal basal cells) expressed higher podoplanin levels than the untreated control cells. The adhesiveness of HaCaT cells, which do not express podoplanin, was reduced after the overexpression of podoplanin. HEK with podoplanin overexpression suppressed the cell adhesion to type I collagen (while downregulating 1-integrin functions) and podoplanin silencing augmented it (by increasing active ECM-bound 1-integrin). The increased cell adhesion to type I collagen induced by podoplanin silencing could be reversed by addition of P5D2, a neutralizing antibody against 1-integrin. In the psoriatic epidermis, podoplanin expression was especially upregulated on the rete ridges of the basal cell layer. This expression pattern was inversely correlated with the total/ECM-bound active 1-integrin-expression, which was stronger at the basal cell layer covering the dermal papillae. Our results indicate that podoplanin inhibits the cell ECM attachment by suppressing 1-integrin and initiating HEK differentiation. Podoplanin is presumably involved in the pathogenesis of psoriasis.