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Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome

Abstract

Deficiency in the serine protease inhibitor LEKTI is the etiological origin of Netherton syndrome, which causes detachment of the stratum corneum and chronic inflammation. Here we show that the membrane protease matriptase initiates Netherton syndrome in a LEKTI-deficient mouse model by premature activation of a pro-kallikrein cascade. Auto-activation of pro-inflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from LEKTI-deficient mice dampened inflammation, eliminated aberrant protease activity, prevented detachment of the stratum corneum, and improved the barrier function of the epidermis. These results uncover a pathogenic matriptase–pro-kallikrein pathway that could operate in several human skin and inflammatory diseases.

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Figure 1: Matriptase and LEKTI co-localize at the site of epidermal separation in Netherton syndrome.
Figure 2: Activation of epidermal pro-kallikreins by matriptase.
Figure 3: Matriptase and prostasin are not inhibitory targets for LEKTI.
Figure 4: Matriptase ablation eliminates aberrant in situ proteolytic activity caused by LEKTI-deficiency.
Figure 5: Matriptase ablation prevents stratum corneum loss and improves the barrier function of LEKTI-deficient epidermis.
Figure 6: Loss of matriptase restores the functional integrity of corneodesmosomes at the granular-transitional layer boundary.
Figure 7: Inflammation in LEKTI-deficient skin requires matriptase.

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Acknowledgements

We thank D. Martin, L. Fisher and L. Wahl for technical assistance, and J. Silvio Gutkind and M. J. Danton for reviewing this manuscript. Support for this study was provided by the NIDCR Intramural Research Program.

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K.U.S. generated recombinant proteins, performed biochemical experiments and analyzed mice with the assistance of K.L. and R.S. A.L.B. and A.L.R. performed mouse breeding and genotyping. A.M. and R.W. helped to conduct confocal fluorescence microscopy analysis. P.A.O. and T.H.B. designed and supervised the study.

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Correspondence to Thomas H Bugge.

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The authors declare no competing financial interests.

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Sales, K., Masedunskas, A., Bey, A. et al. Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nat Genet 42, 676–683 (2010). https://doi.org/10.1038/ng.629

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