Inhibition of Rho A activity causes pemphigus skin blistering.
The autoimmune blistering skin diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are mainly caused by autoantibodies against desmosomal cadherins. In this study, we provide evidence that PV-immunoglobulin G (IgG) and PF-IgG induce skin blistering by interference with Rho A signaling. In vitro, pemphigus IgG caused typical hallmarks of pemphigus pathogenesis such as epidermal blistering in human skin, cell dissociation, and loss of desmoglein 1 (Dsg 1)-mediated binding probed by laser tweezers. These changes were accompanied by interference with Rho A activation and reduction of Rho A activity. Pemphigus IgG-triggered keratinocyte dissociation and Rho A inactivation were p38 mitogen-activated protein kinase dependent. Specific activation of Rho A by cytotoxic necrotizing factor-y abolished all pemphigus-triggered effects, including keratin retraction and release of Dsg 3 from the cytoskeleton. These data demonstrate that Rho A is involved in the regulation of desmosomal adhesion, at least in part by maintaining the cytoskeletal anchorage of desmosomal proteins. This may open the possibility of pemphigus treatment with the epidermal application of Rho A agonists.
Waschke
Jens
J
Institute of Anatomy and Cell Biology, University of Würzburg, D-97070 Würzburg, Germany. jens.waschke@mail.uni-wuerzburg.de
Spindler
Volker
V
Bruggeman
Paola
P
Zillikens
Detlef
D
Schmidt
Gudula
G
Drenckhahn
Detlev
D
D001768:Blister / Q000201:enzymology / Q000209:etiology*; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D051183:Desmoglein 1 / Q000378:metabolism; D051184:Desmoglein 3 / Q000378:metabolism; D003896:Desmosomes / Q000201:enzymology / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology*; D053547:Keratin-14 / Q000378:metabolism; D015603:Keratinocytes / Q000473:pathology; D010392:Pemphigus / Q000201:enzymology / Q000209:etiology* / Q000276:immunology; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D015820:Cadherins; C495297:DSG1 protein, human; C071894:DSG3 protein, human; D051183:Desmoglein 1; D051184:Desmoglein 3; D007074:Immunoglobulin G; D053547:Keratin-14; D020742:rhoA GTP-Binding Protein