BP180 dysfunction triggers spontaneous skin inflammation in mice

Significance BP180 is a cell–cell matrix adhesion molecule and is critical for attachment of epidermis to underlying dermis. We generated a dysfunctional BP180 mouse strain (ΔNC16A mice). The ΔNC16A mice at 8 weeks start developing spontaneous itch and skin inflammation characterized by increased skin thickness, infiltrating immune cells, increased levels of IgE in circulation, proinflammatory mediators in the skin, and impaired skin barrier. Bullous pemphigoid (BP) patients also present increased TSLP in lesional skin and circulation. Our findings suggest that BP180 regulates pruritic skin inflammation. Elucidation of molecular and cellular mechanisms underlying the role of BP180 in skin inflammation should help better understanding of pathophysiology of skin inflammation and identify therapeutic targets for skin inflammatory diseases such as BP and atopic dermatitis. 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 ΔNC16A) 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.

[1]  K. Amber,et al.  Autoimmune Subepidermal Bullous Diseases of the Skin and Mucosae: Clinical Features, Diagnosis, and Management , 2018, Clinical Reviews in Allergy & Immunology.

[2]  Kachiu C. Lee,et al.  Case Series Study of the Efficacy of Compounded Antibacterial, Steroid, and Moisturizer in Atopic Dermatitis , 2017, Pediatric dermatology.

[3]  Y. Tokura,et al.  Management of erythematous skin lesions in bullous pemphigoid associated with atopic dermatitis , 2016, The Journal of dermatology.

[4]  J. Teng,et al.  Advancement in management of epidermolysis bullosa , 2016, Current opinion in pediatrics.

[5]  C. Hammers,et al.  Mechanisms of Disease: Pemphigus and Bullous Pemphigoid. , 2016, Annual review of pathology.

[6]  H. Williams,et al.  A randomized controlled trial to compare the safety and effectiveness of doxycycline (200 mg daily) with oral prednisolone (0·5 mg kg−1 daily) for initial treatment of bullous pemphigoid: a protocol for the Bullous Pemphigoid Steroids and Tetracyclines (BLISTER) Trial , 2015, The British journal of dermatology.

[7]  J. Jacków,et al.  Deletion of the major bullous pemphigoid epitope region of collagen XVII induces blistering, autoimmunization, and itching in mice. , 2015, The Journal of investigative dermatology.

[8]  M. Babina,et al.  Thymic stromal lymphopoietin induction by skin irritation is independent of tumour necrosis factor‐α, but supported by interleukin‐1 , 2015, The British journal of dermatology.

[9]  P. Moons,et al.  Burden of itch in epidermolysis bullosa , 2014, The British journal of dermatology.

[10]  F. Nestle,et al.  Mechanisms regulating skin immunity and inflammation , 2014, Nature Reviews Immunology.

[11]  M. Hoon,et al.  Why we scratch an itch: the molecules, cells and circuits of itch , 2014, Nature Neuroscience.

[12]  A. Lowe,et al.  Atopic dermatitis and the atopic march revisited , 2014, Allergy.

[13]  M. Pellegrino,et al.  The Epithelial Cell-Derived Atopic Dermatitis Cytokine TSLP Activates Neurons to Induce Itch , 2013, Cell.

[14]  J. Ring,et al.  A case of junctional epidermolysis bullosa with prurigo‐like lesions and reduction of collagen XVII and filaggrin , 2013, The British journal of dermatology.

[15]  S. Ziegler.  Thymic stromal lymphopoietin and allergic disease. , 2012, The Journal of allergy and clinical immunology.

[16]  J. McGrath,et al.  Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa. , 2012, Cancer research.

[17]  M. Little,et al.  Abstract 3522: Preclinical development of an anti-CD30/anti-CD16A bispecific tetravalent TandAb antibody for the treatment of Hodgkin lymphoma , 2012 .

[18]  Hui Wang,et al.  A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch , 2012, NeuroImage.

[19]  Yanlu Zhang,et al.  Functions of thymic stromal lymphopoietin in immunity and disease , 2012, Immunologic research.

[20]  D. Murrell,et al.  Inherited epidermolysis bullosa: new diagnostic criteria and classification. , 2012, Clinics in dermatology.

[21]  M. Boguniewicz,et al.  Atopic dermatitis: a disease of altered skin barrier and immune dysregulation , 2011, Immunological reviews.

[22]  C. Has,et al.  Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa , 2011, Journal of Medical Genetics.

[23]  J. Fine.  Inherited epidermolysis bullosa , 2010, Orphanet journal of rare diseases.

[24]  Y. Matsuzaki,et al.  Overview of epidermolysis bullosa , 2010, The Journal of dermatology.

[25]  C. Has,et al.  Collagen XVII. , 2010, Dermatologic clinics.

[26]  P. Dubus,et al.  Kallikrein 5 induces atopic dermatitis–like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome , 2009, The Journal of experimental medicine.

[27]  H. Stark,et al.  Histamine H4 receptor antagonism reduces hapten‐induced scratching behaviour but not inflammation , 2009, Experimental dermatology.

[28]  Detlef Zillikens,et al.  Subepidermal blistering induced by human autoantibodies to BP180 requires innate immune players in a humanized bullous pemphigoid mouse model. , 2008, Journal of autoimmunity.

[29]  S. Ziegler,et al.  TSLP acts on infiltrating effector T cells to drive allergic skin inflammation , 2008, Proceedings of the National Academy of Sciences.

[30]  H. Murota,et al.  Oral steroid improves bullous pemphigoid‐like clinical manifestations in non‐Herlitz junctional epidermolysis bullosa with COL17A1 mutation , 2007, The British journal of dermatology.

[31]  P. Chambon,et al.  Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[32]  P. Chambon,et al.  Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Ziegler,et al.  Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin , 2005, The Journal of experimental medicine.

[34]  J. Saurat,et al.  Childhood Bullous Pemphigoid: Report of a Case with Life‐Threatening Course During Homeopathy Treatment , 2004, Pediatric dermatology.

[35]  A. Sonnenberg,et al.  Analysis of the interactions between BP180, BP230, plectin and the integrin α6β4 important for hemidesmosome assembly , 2003, Journal of Cell Science.

[36]  J. Bauer,et al.  Type XVII collagen gene mutations in junctional epidermolysis bullosa and prospects for gene therapy , 2003, Clinical and experimental dermatology.

[37]  M. Fortini,et al.  Signalling: γ-Secretase-mediated proteolysis in cell-surface-receptor signalling , 2002, Nature Reviews Molecular Cell Biology.

[38]  A. Taïeb,et al.  Atopic dermatitis: therapeutic challenge in an infant with dystrophic epidermolysis bullosa , 2002, The British journal of dermatology.

[39]  Kathleen M. Smith,et al.  Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP , 2002, Nature Immunology.

[40]  R. Sheridan,et al.  Junctional epidermolysis bullosa: diagnosis and management of a patient with the Herlitz variant. , 1998, Journal of pediatric surgery.

[41]  L. Diaz,et al.  Autoimmune response against the bullous pemphigoid 180 autoantigen. , 1994, Dermatology.

[42]  J. Troy,et al.  A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. , 1993, The Journal of clinical investigation.

[43]  D. Stevanović.  Inherited epidermolysis bullosa. , 1992, Journal of the American Academy of Dermatology.

[44]  I I Lelis,et al.  [Atopic dermatitis]. , 1980, Vestnik dermatologii i venerologii.