Meprin proteases in cutaneous homeostasis and psoriasis: pathophysiological mechanisms and therapeutic prospects

Psoriasis is a chronic immune-mediated inflammatory disorder characterized by epidermal hyperplasia, barrier dysfunction, and dysregulated crosstalk between keratinocytes and adaptive immune cells. Although the IL-23/IL-17 axis remains central to disease pathogenesis, the extracellular mechanisms that sustain and amplify inflammation are not well defined. Emerging evidence highlights extracellular proteolysis as a critical regulator of inflammatory persistence in psoriatic skin by modulating cytokine bioavailability, receptor activation, extracellular matrix remodeling, and immune cell trafficking, including the release of angiogenic mediators such as VEGF. Zinc-dependent metalloproteases are key contributors to these processes. Among them, meprin α and meprin β exhibit distinct structural and spatial characteristics, positioning them as context-dependent regulators of epithelial and immune homeostasis. In psoriatic lesions, meprin α overexpression results in keratinocyte hyperproliferation, barrier deficiencies with increased transepidermal water loss, and local inflammation due to the proteolytic cleavage of dermokine, an essential regulator of immune responses and epidermal differentiation. Additionally, it is mislocalized to the suprabasal layers. Meprin-α has also been shown to synchronize the activation of skin barrier proteins, effectively contributing to sustained barrier integrity. This, together with the pathogenic repercussions of the meprin-driven pro-inflammatory milieu, has far-reaching implications for this understudied protein. Thus, the current review synthesizes evidence implicating meprins in keratinocyte differentiation, barrier integrity, cytokine processing, and matrix remodeling. We further discuss the regulatory mechanisms that control meprin expression and evaluate its therapeutic potential as an upstream modulator of extracellular inflammatory signaling in psoriasis.