Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ

JS Ainscough, T Macleod, D McGonagle… - Proceedings of the …, 2017 - pnas.org
JS Ainscough, T Macleod, D McGonagle, R Brakefield, JM Baron, A Alase, M Wittmann
Proceedings of the national academy of sciences, 2017pnas.org
The proinflammatory cytokine IL-36γ is highly expressed in epithelial cells and is a pivotal
mediator of epithelial inflammation. In particular, IL-36γ is strongly associated with the
inflammatory skin disease psoriasis. As with other IL-1 cytokines, IL-36γ is expressed as an
inactive precursor and must be processed by specific proteases to become bioactive. Our
aim therefore was to identify protease/s capable of IL-36γ activation and explore the
importance of this activation in psoriasis. Using a keratinocyte-based activity assay in …
The proinflammatory cytokine IL-36γ is highly expressed in epithelial cells and is a pivotal mediator of epithelial inflammation. In particular, IL-36γ is strongly associated with the inflammatory skin disease psoriasis. As with other IL-1 cytokines, IL-36γ is expressed as an inactive precursor and must be processed by specific proteases to become bioactive. Our aim therefore was to identify protease/s capable of IL-36γ activation and explore the importance of this activation in psoriasis. Using a keratinocyte-based activity assay in conjunction with small-molecule inhibitors and siRNA gene silencing, cathepsin S was identified as the major IL-36γ–activating protease expressed by epithelial cells. Interestingly, cathepsin S activity was strongly up-regulated in samples extracted from psoriasis patients relative to healthy controls. In addition, IL-36γ–Ser18, identified as the main product of cathepsin S-dependent IL-36γ cleavage, induced psoriasiform changes in human skin-equivalent models. Together, these data provide important mechanistic insights into the activation of IL-36γ and highlight that cathepsin S-mediated activation of IL-36γ may be important in the development of numerous IL-36γ–driven pathologies, in addition to psoriasis.
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