Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA.
Department of Dermatology, University of California, San Diego, San Diego, CA 92093, USA; SILAB, R&D Department, Brive, France.
Cell Rep. 2020 Mar 3;30(9):2923-2933.e7. doi: 10.1016/j.celrep.2020.02.021.
Netherton syndrome (NS) is a monogenic skin disease resulting from loss of function of lymphoepithelial Kazal-type-related protease inhibitor (LEKTI-1). In this study we examine if bacteria residing on the skin are influenced by the loss of LEKTI-1 and if interaction between this human gene and resident bacteria contributes to skin disease. Shotgun sequencing of the skin microbiome demonstrates that lesional skin of NS subjects is dominated by Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). Isolates of either species from NS subjects are able to induce skin inflammation and barrier damage on mice. These microbes promote skin inflammation in the setting of LEKTI-1 deficiency due to excess proteolytic activity promoted by S. aureus phenol-soluble modulin α as well as increased bacterial proteases staphopain A and B from S. aureus or EcpA from S. epidermidis. These findings demonstrate the critical need for maintaining homeostasis of host and microbial proteases to prevent a human skin disease.
Netherton 综合征（NS）是一种单基因皮肤疾病，由淋巴上皮 Kazal 型相关蛋白酶抑制剂（LEKTI-1）功能丧失引起。在这项研究中，我们研究了皮肤上的细菌是否会受到 LEKTI-1 缺失的影响，以及人类基因与常驻细菌之间的相互作用是否会导致皮肤疾病。皮肤微生物组的鸟枪法测序表明，NS 患者的皮损皮肤主要由金黄色葡萄球菌（S. aureus）和表皮葡萄球菌（S. epidermidis）定植。从 NS 患者中分离的这两种细菌都能够在小鼠身上诱导皮肤炎症和屏障损伤。由于金黄色葡萄球菌酚可溶性调节素 α（phenol-soluble modulin α）促进的过度蛋白水解活性，以及金黄色葡萄球菌或表皮葡萄球菌的 staphopain A 和 B 或表皮葡萄球菌的 EcpA 等细菌蛋白酶的增加，这些微生物在 LEKTI-1 缺乏的情况下促进了皮肤炎症。这些发现表明，为了预防人类皮肤疾病，维持宿主和微生物蛋白酶的内稳态至关重要。
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