Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome
被引:372
作者:
Briot, Anais
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机构:
Fac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Univ Toulouse 3, F-31400 Toulouse, FranceFac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Briot, Anais
[1
,2
]
Deraison, Celine
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机构:
Fac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Univ Toulouse 3, F-31400 Toulouse, France
Ctr Hosp Univ Toulouse, Hop Purpan, Dept Med Genet, F-31000 Toulouse, FranceFac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Deraison, Celine
[1
,2
,3
]
Lacroix, Matthieu
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机构:
Fac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Univ Toulouse 3, F-31400 Toulouse, FranceFac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Lacroix, Matthieu
[1
,2
]
Bonnart, Chrystelle
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机构:
Fac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Univ Toulouse 3, F-31400 Toulouse, FranceFac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Bonnart, Chrystelle
[1
,2
]
Robin, Aurelie
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机构:
Fac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Univ Toulouse 3, F-31400 Toulouse, FranceFac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Robin, Aurelie
[1
,2
]
Besson, Celine
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机构:
Fac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Univ Toulouse 3, F-31400 Toulouse, FranceFac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Besson, Celine
[1
,2
]
Dubus, Pierre
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机构:
Univ Bordeaux 2, EA2406, F-33076 Bordeaux, FranceFac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Dubus, Pierre
[4
]
Hovnanian, Alain
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h-index: 0
机构:
Fac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Univ Toulouse 3, F-31400 Toulouse, France
Ctr Hosp Univ Toulouse, Hop Purpan, Dept Med Genet, F-31000 Toulouse, FranceFac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
Hovnanian, Alain
[1
,2
,3
]
机构:
[1] Fac Med Toulouse, INSERM, U563, F-31300 Toulouse, France
[2] Univ Toulouse 3, F-31400 Toulouse, France
[3] Ctr Hosp Univ Toulouse, Hop Purpan, Dept Med Genet, F-31000 Toulouse, France
[4] Univ Bordeaux 2, EA2406, F-33076 Bordeaux, France
PROTEINASE-ACTIVATED RECEPTOR-2;
SERINE-PROTEASE INHIBITOR;
HUMAN EPITHELIAL-CELLS;
NF-KAPPA-B;
STRATUM-CORNEUM;
MAST-CELLS;
HUMAN SKIN;
EPIDERMAL-KERATINOCYTES;
ALLERGIC INFLAMMATION;
CYTOKINE PRODUCTION;
D O I:
10.1084/jem.20082242
中图分类号:
R392 [医学免疫学];
Q939.91 [免疫学];
学科分类号:
100102 ;
摘要:
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 kappa B-mediated overexpression of TSLP, intercellular adhesion molecule 1, tumor necrosis factor alpha, 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.