Pathological meprin alpha expression as a driver of inflammatory skin disease
The skin is the largest organ and the body’s outermost barrier, with the epidermis as its outermost layer. The epidermis consists of distinct layers composed of keratinocytes at different stages of terminal differentiation. This process is orchestrated by a network of epidermal proteases, which require tight regulation. Any changes to any of these factors could lead to dysregulation of the epidermal protease network and result in the development of pathological conditions, such as ichthyoses, a family of keratinization disorders. In general, keratinocytes play a key role in such pathologies, as they are affected by a dysregulated protease web and can also contribute to its dysregulation. Therefore, it is necessary to understand keratinocyte biology and to identify proteases and their substrates, which contribute to the regulation of keratinocytes within the epidermis. In this context, the metalloprotease meprin a was shown to be upregulated and mislocalized in patients with psoriasis vulgaris and Netherton syndrome. Under healthy conditions, meprin a is expressed by keratinocytes of the stratum basale (SB), suggesting a potential function of meprin a in the regulation of keratinocyte proliferation. Although there is mechanistic evidence for a functional role of meprin a in dermal wound healing, little is known about its role and substrates within the epidermis. Therefore, the aim of this thesis was to investigate the role of meprin a by identifying epidermal substrates of the protease. To achieve this goal, the genetically modified K5Ma mouse model was employed, which enabled the inducible overexpression of meprin a in keratinocytes of the SB. Upon overexpression, these mice developed a severe skin phenotype. Examination of this phenotype showed that it was characterized by hyperproliferative keratinocytes, followed by the disruption of the skin’s barrier integrity and the induction of an immune response, mainly driven by infiltrating neutrophils. Dermokine was identified as a substrate of meprin a in the skin of K5Ma mice and the cleavage of dermokine by meprin a could help to explain the development of the severe skin phenotype of K5Ma mice, as dermokine has been shown to regulate keratinocyte proliferation and inflammatory signaling.
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