Neural nitric oxide synthase participates in pemphigus vulgaris acantholysis through upregulation of Rous sarcoma, mammalian target of rapamycin and focal adhesion kinase

Pemphigus vulgaris (PV) is an autoimmune blistering skin disease characterized by suprabasal acantholysis produced as a consequence of desmoglein (Dsg) and non‐Dsg autoantibodies binding to several targeting molecules localized on the membrane of keratinocytes. Nitric oxide (NO) may exert a pathogen...

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Bibliographic Details
Published in:Experimental dermatology 2013-02, Vol.22 (2), p.125-130
Main Authors: España, Agustín, Mòdol, Teresa, Gil, Maria P., López-Zabalza, Maria J.
Format: Article
Language:English
Subjects:
acantholysis
Acantholysis - enzymology
Animal models
Animals
Biopsy
cantholysis
Caspase 3 - metabolism
Caspase 9 - metabolism
Female
Focal Adhesion Protein-Tyrosine Kinases - metabolism
Gene Expression Profiling
Gene Expression Regulation, Enzymologic
Humans
Immunoglobulin G - immunology
immunoglobuline G
Male
Mice
Mice, Inbred C57BL
mouse model
nitric oxide synthase
Nitric Oxide Synthase Type I - metabolism
Pemphigus - enzymology
pemphigus vulgaris
Rous sarcoma
src-Family Kinases - metabolism
Time Factors
TOR Serine-Threonine Kinases - metabolism
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Summary:Pemphigus vulgaris (PV) is an autoimmune blistering skin disease characterized by suprabasal acantholysis produced as a consequence of desmoglein (Dsg) and non‐Dsg autoantibodies binding to several targeting molecules localized on the membrane of keratinocytes. Nitric oxide (NO) may exert a pathogenic function in several immunological processes. We have previously demonstrated that neural nitric oxide synthase (nNOS) plays part in PV acantholysis. Also, our group has described a relevant role for HER [human epidermal growth factor receptor (EGFR) related] isoforms and several kinases such as Src (Rous sarcoma), mammalian target of rapamycin (mTOR) and focal adhesion kinase (FAK), as well as caspases in PV development. Using a passive transfer mouse model of PV, we aimed to investigate the relationship between the increase in nNOS and EGFR, Src, mTOR and FAK kinase upregulation observed in PV lesions. Our results revealed a new function for nNOS, which contributes to EGFR‐mediated PV acantholysis through the upregulation of Src, mTOR and FAK. In addition, we found that nNOS participates actively in PV at least in part by increasing caspase‐9 and caspase‐3 activities. These findings underline the important issue that in PV acantholysis, caspase activation is a nNOS‐linked process downstream of Src, mTOR and FAK kinase upregulation.
ISSN:0906-6705
1600-0625
DOI:10.1111/exd.12088