• Meprins subtly support epidermal and dermal skin wound healing. • Loss of both meprins reduces re-epithelialization and wound macrophage abundance. • Meprin α is a physiological maturing proteinase of collagen VII. • Meprins are reduced in recessive dystrophic epidermolysis bullosa skin.

Age-related macular degeneration (AMD) is a progressive disease of the macula characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor degeneration, leading to severe vision loss at advanced stages in the elderly population. Impaired reverse cholesterol transport (RCT) as well as intracellular lipid accumulation in the RPE are implicated in AMD pathogenesis. Here, we focus on ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transport protein in the RPE, and analyze conditions that lead to ABCA1 dysregulation in induced pluripotent stem cell (iPSC)-derived RPE cells (iRPEs). Our results indicate that the risk-conferring alleles rs1883025 (C) and rs2740488 (A) in ABCA1 are associated with increased ABCA1 mRNA and protein levels and reduced efficiency of cholesterol efflux from the RPE. Hypoxia, an environmental risk factor for AMD, reduced expression of ABCA1 and increased intracellular lipid accumulation. Treatment with a liver X receptor (LXR) agonist led to an increase in ABCA1 expression and reduced lipid accumulation. Our data strengthen the homeostatic role of cholesterol efflux in the RPE and suggest that increasing cellular cholesterol export by stimulating ABCA1 expression might lessen lipid load, improving RPE survival and reducing the risk of developing AMD.

Keratinocyte proliferation and differentiation is regulated via proteolytic networks. Dysregulation of proteases within these networks can cause hyperproliferative and inflammatory skin disorders. In healthy skin the metalloprotease meprin α is localized in the stratum basale . In contrast, in wound healing tissue and psoriatic lesions increased meprin α levels are found in the upper epidermal layers. We developed a transgenic mouse model for inducible expression of pathological meprin α levels (K5Mα) to investigate its epidermal degradome and identify molecular links to keratinocyte proliferation and skin inflammation. K5Mα mice developed a severe skin phenotype characterized by hyperkeratosis, acanthosis and parakeratosis accompanied by increased transepidermal water loss and a strong inflammatory response within six days after induction of meprin α overexpression. Histological and molecular analyses showed that increasing meprin α expression correlates with meprin α activity and keratinocyte hyperproliferation. Proteomics analyses revealed massive changes in proteins associated with keratinocyte differentiation and epidermal barrier integrity already three days after induction. N-terminomics data indicated a dominant chymotryptic activity with elevated proteolytic turnover of proteins associated with the cytoskeleton, cellular stress responses and cell adhesion. By filtering for cleavage sites that match with the specificity of meprin α, we identified highly elevated dermokine-derived peptides. Subsequent mass spectrometric analyses validated dermokine as a novel substrate of meprin α and identified the cleavage site, which is highly conserved in mammals. Based on the striking similarities with the phenotype reported for dermokine αβγ ^-/- mice, we propose meprin α as a central regulator of keratinocyte proliferation and leukocyte recruitment by proteolytic inactivation of dermokine. Hence, pathological meprin α activity could be a driver of hyperproliferative, inflammatory skin disorders like psoriasis vulgaris.