Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome.
Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome.
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DOI：
10.1084/jem.20082242
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发表时间：
2009-05-11
期刊：
影响因子：
--
通讯作者：
Hovnanian A
中科院分区：
文献类型：
--
作者：
Briot A;Deraison C;Lacroix M;Bonnart C;Robin A;Besson C;Dubus P;Hovnanian A
内瑟顿综合征（NS）是一种严重的遗传性皮肤病，具有持续的特应性表现，由丝氨酸蛋白酶抑制剂Kazal-5型（SPINK 5）基因突变引起，该基因编码蛋白酶抑制剂淋巴上皮Kazal-型相关抑制剂（LEKTI）。缺乏LEKTI会导致继发于表皮蛋白酶活性亢进的角质层脱离。这种皮肤屏障缺陷有利于过敏原吸收，通常被认为是NS中特应性的根本原因。我们首次表明，前Th 2细胞因子胸腺基质淋巴细胞生成素（TSLP），胸腺和活化调节趋化因子，巨噬细胞衍生的趋化因子在LEKTI缺陷的表皮过表达。这是原始生物级联反应的一部分，其中未调节的激肽释放酶（KLK）5直接激活蛋白酶激活受体2，并诱导核因子κ B介导的TSLP、细胞间粘附分子1、肿瘤坏死因子α和IL 8过表达。这种促炎和促过敏途径独立于原发性上皮衰竭，并在NS角质形成细胞的基础条件下被激活。这种细胞自主过程已经在Spink 5 −/−胚胎的表皮中建立，并且由此产生的促炎微环境导致裸鼠皮肤移植模型中的嗜酸性细胞和肥大细胞浸润。总的来说，这些数据确定NS表皮中不受控制的KLK 5活性可以独立于环境和适应性免疫系统触发特应性皮炎（AD）样病变。他们阐明了蛋白酶信号在皮肤炎症中的关键作用，并指出了NS的新治疗靶点以及AD和特应性的候选基因。
Netherton syndrome (NS) is a severe genetic skin disease with constant atopic manifestations that is caused by mutations in the serine protease inhibitor Kazal-type 5 (SPINK5) gene, which encodes the protease inhibitor lymphoepithelial Kazal-type–related inhibitor (LEKTI). Lack of LEKTI causes stratum corneum detachment secondary to epidermal proteases hyperactivity. This skin barrier defect favors allergen absorption and is generally regarded as the underlying cause for atopy in NS. We show for the first time that the pro-Th2 cytokine thymic stromal lymphopoietin (TSLP), the thymus and activation-regulated chemokine, and the macrophage-derived chemokine are overexpressed in LEKTI-deficient epidermis. This is part of an original biological cascade in which unregulated kallikrein (KLK) 5 directly activates proteinase-activated receptor 2 and induces nuclear factor κB–mediated overexpression of TSLP, intercellular adhesion molecule 1, tumor necrosis factor α, and IL8. This proinflammatory and proallergic pathway is independent of the primary epithelial failure and is activated under basal conditions in NS keratinocytes. This cell-autonomous process is already established in the epidermis of Spink5−/− embryos, and the resulting proinflammatory microenvironment leads to eosinophilic and mast cell infiltration in a skin graft model in nude mice. Collectively, these data establish that uncontrolled KLK5 activity in NS epidermis can trigger atopic dermatitis (AD)–like lesions, independently of the environment and the adaptive immune system. They illustrate the crucial role of protease signaling in skin inflammation and point to new therapeutic targets for NS as well as candidate genes for AD and atopy.
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DOI：
10.1084/jem.20062211
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Allakhverdi Z;Comeau MR;Jessup HK;Yoon BR;Brewer A;Chartier S;Paquette N;Ziegler SF;Sarfati M;Delespesse G
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Delespesse G
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30.8
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