Role of Spink6 in tissue kallikrein mediated epidermal desquamation and inflammation

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Proteases of the KLK-family (Kallikrein related peptidases) have been implicated in the desquamation process of healthy human skin by cleaving desmosomal proteins. Their activity is tightly regulated by different mechanisms including specific protease inhibitors. Deregulation can lead to serious inflammatory diseases like the Netherton Syndrome, where the KLK-specific inhibitor LEKTI (lymphoepithelial inhibitor of Kazal-type) encoded by the gene spink5 (serine protease inhibitor of Kazal-type) is missing. The increased proteolytic activity leads to activation of the protease activated receptor-2, increased activation of proinflammatory products of the alarmin cathelicidin and to enhanced processing of members of the IL-1 family. In previous studies we have discovered two novel members of the SPINK family in human skin, namely SPINK6 and SPINK9. SPINK9 is a selective KLK5 inhibitor, whereas SPINK6 is the most potent inhibitor of several KLKs described so far. We characterized their mouse homologues as mouse mouse Spink12 for human SPINK9 and the highly conserved mouse Spink6 (homologue to human SPINK6). The inhibition profile of mouse Spink6 was similar to human SPINK6 but exhibited some differences, e.g. KLK4 was not inhibited by the human but very efficiently by the mouse Spink6. Interestingly, we detected cleavage of IL-1 family members like IL-36gamma by KLKs. KLK7 cleaved IL-36gamma within seconds whereas IL-36gamma cleavage by the tryptic KLK5 took hours. We suspect a regulatory mechanism by different KLKs for IL-36gamma activation in the epidermis. We therefore plan to further analyze the mechanism by which KLKs cleave IL-1 family members like IL-36gamma and want to explore the role of Klk-regulation by Spink6 using Spink6-/- mice in vivo.