BP180 dysfunction triggers spontaneous skin inflammation in mice

Abstract

BP180, also known as collagen XVII, is a hemidesmosomal component and plays a key role in maintaining skin dermal/epidermal adhesion. Dysfunction of BP180, either through genetic mutations in junctional epidermolysis bullosa (JEB) or autoantibody insult in bullous pemphigoid (BP), leads to subepidermal blistering accompanied by skin inflammation. However, whether BP180 is involved in skin inflammation remains unknown. To address this question, we generated a BP180-dysfunctional mouse strain and found that mice lacking functional BP180 (termed Δ) developed spontaneous skin inflammatory disease, characterized by severe itch, defective skin barrier, infiltrating immune cells, elevated serum IgE levels, and increased expression of thymic stromal lymphopoietin (TSLP). Severe itch is independent of adaptive immunity and histamine, but dependent on increased expression of TSLP by keratinocytes. In addition, a high TSLP expression is detected in BP patients. Our data provide direct evidence showing that BP180 regulates skin inflammation independently of adaptive immunity, and BP180 dysfunction leads to a TSLP-mediated itch. The newly developed mouse strain could be a model for elucidation of disease mechanisms and development of novel therapeutic strategies for skin inflammation and BP180-related skin conditions.

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

“…Bullous pemphigoid (BP) is an IgG-mediated autoimmune disease resulting in skin blisters [273]. In mice, BP is induced by injection of the hemidesmosome antigen BP180 mediating accumulation of CD11b + cells in the skin that confer inflammatory reactions [274]. In CD11b −/− mice the development of BP in mice was significantly lower as compared with WT mice, since CD11b −/− PMN could not efficiently infiltrate the skin [275].…”

The dysfunction of BP180/collagen XVII in keratinocytes promotes melanoma progression

“…Our lab purposely flanked the NC16A-encoding sequence with loxP sites 10 . As we crossed the humanized NC16A mice with mice carrying different promoter-driven Cre genes, we generated systemic or conditional NC16A deficient mice (termed ∆NC16A) 21 . The ∆NC16A mice can live up to one year after birth, which provided a valuable tool to investigate a role of BP180 other than as a cell/ECM adhesion molecule 21 .…”

The Role of Collagen XVII in Cancer: Squamous Cell Carcinoma and Beyond

“…Nonetheless, a direct role of collagen XVII in skin inflammation is unclear. In a humanized NC16A mouse, mutation induced dysfunction of NC16A in basal keratinocytes (termed NC16A), leads to development of spontaneous skin inflammatory disease (49). These mice exhibit severe pruritus, dysfunctional skin barrier, infiltrating immune cells, increased serum IgE levels, and high expression of thymic stromal lymphopoietin (TSLP) (49).…”

“…In a humanized NC16A mouse, mutation induced dysfunction of NC16A in basal keratinocytes (termed NC16A), leads to development of spontaneous skin inflammatory disease (49). These mice exhibit severe pruritus, dysfunctional skin barrier, infiltrating immune cells, increased serum IgE levels, and high expression of thymic stromal lymphopoietin (TSLP) (49). Severe pruritus is not mediated by adaptive immunity or histamine, rather, it is dependent on increased expression of TSLP (49).…”

“…These mice exhibit severe pruritus, dysfunctional skin barrier, infiltrating immune cells, increased serum IgE levels, and high expression of thymic stromal lymphopoietin (TSLP) (49). Severe pruritus is not mediated by adaptive immunity or histamine, rather, it is dependent on increased expression of TSLP (49).…”