In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades

Sánchez‐Carpintero, I.; España, A.; Pelacho, Beatriz; Moratalla, Natalia López; Rubenstein, David S.; Díaz, Luis A.; López-Zabalza, Marı́a J.

doi:10.1111/j.1365-2133.2004.06147.x

Cited by 78 publications

(93 citation statements)

References 30 publications

(43 reference statements)

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“…In this regard, inhibition of Dsg3 internalization and/or desmosomal disassembly may serve as potential targets for PV therapeutics. In fact, genistein was recently reported to prevent blistering in a mouse model of PV (65). Although genistein may exert effects on the desmosome independent from the regulation of Dsg3 endocytosis, these and other studies (20,(65)(66)(67) highlight the possibility that PV blistering in patients might be treated by pharmacological strategies that target keratinocyte responses to PV IgG.…”

Section: Discussionmentioning

confidence: 99%

Pemphigus Vulgaris IgG-induced Desmoglein-3 Endocytosis and Desmosomal Disassembly Are Mediated by a Clathrin- and Dynamin-independent Mechanism

Delva

Jennings

Calkins

et al. 2008

Journal of Biological Chemistry

117

130

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Pemphigus vulgaris (PV) is a life-threatening autoimmune disease characterized by oral mucosal erosions and epidermal blistering. The autoantibodies generated target the desmosomal cadherin desmoglein-3 (Dsg3). Previous studies demonstrate that upon PV IgG binding, Dsg3 is internalized and enters an endo-lysosomal pathway where it is degraded. To define the endocytic machinery involved in PV IgG-induced Dsg3 internalization, human keratinocytes were incubated with PV IgG, and various tools were used to perturb distinct endocytic pathways. The PV IgG⅐Dsg3 complex failed to colocalize with clathrin, and inhibitors of clathrin-and dynamin-dependent pathways had little or no effect on Dsg3 internalization. In contrast, cholesterol binding agents such as filipin and nystatin and the tyrosine kinase inhibitor genistein dramatically inhibited Dsg3 internalization. Furthermore, the Dsg3 cytoplasmic tail specified sensitivity to these inhibitors. Moreover, inhibition of Dsg3 endocytosis with genistein prevented disruption of desmosomes and loss of adhesion in the presence of PV IgG. Altogether, these results suggest that PV IgG-induced Dsg3 internalization is mediated through a clathrin-and dynamin-independent pathway and that Dsg3 endocytosis is tightly coupled to the pathogenic activity of PV IgG.Desmosomes are adhesive junctions that provide robust adhesion between epithelial cells (1, 2). These organelles are prominent in tissues that experience substantial mechanical stress such as the heart, bladder, gastrointestinal mucosa, and skin. Desmosomes are comprised primarily of proteins from three major families, the desmosomal cadherins desmogleins and desmocollins, armadillo proteins such as plakoglobin and the plakophilins, and members of the plakin family of cytolinkers such as desmoplakin (1-3). Together, these proteins contribute to tissue integrity by coupling adhesive interactions mediated by the desmosomal cadherins to the keratin intermediate filament cytoskeleton, thereby integrating adhesive and cytoskeletal networks throughout the cells in a tissue. Although critical for tissue integrity, desmosomes are often remodeled and contribute to dynamic processes during development and wound healing. Furthermore, desmosomal components may also play pivotal roles in keratinocyte differentiation, morphogenesis, and tissue patterning as well as epithelial-mesenchymal transitions (4, 5).Pemphigus vulgaris (PV) 2 is a potentially fatal autoimmune skin disease in which autoantibodies are generated against the desmosomal cadherin, desmoglein-3 (Dsg3) (6 -8). Dsg3, a 130-kDa glycoprotein, is found primarily in the spinous and basal layers of the epidermis and throughout the oral mucosa (9). As a result, PV is characterized histologically by suprabasal loss of cell-cell adhesion (acantholysis) and clinically by blistering of the skin and erosion of mucous membranes (7,8). A wide range of approaches have demonstrated that Dsg3 is the key target of PV IgG (10, 11). In addition, experimentally generated mice in which the Dsg3 ge...

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Section: Discussionmentioning

confidence: 99%

Pemphigus Vulgaris IgG-induced Desmoglein-3 Endocytosis and Desmosomal Disassembly Are Mediated by a Clathrin- and Dynamin-independent Mechanism

Delva

Jennings

Calkins

et al. 2008

Journal of Biological Chemistry

117

130

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“…The in vitro and in vivo studies revealed not only the complexity of PVIgG signaling, but also clearly demonstrated the therapeutic potential of kinase inhibitors and pathway modifiers. PVIgG-dependent acantholysis in experimental animals could be ameliorated by inhibitors of phospholipase C, protein kinase C, p38 MAPK, other tyrosine kinases, calmodulin as well as cholinergic agonists (7)(8)(9). The triggering events, however, remain obscure.…”

Section: Pemphigus Vulgaris (Pv)mentioning

confidence: 98%

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Chernyavsky

Arredondo

Kitajima

et al. 2007

Journal of Biological Chemistry

127

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Although it is accepted that pemphigus antibody binding to keratinocytes (KCs) evokes an array of intracellular biochemical events resulting in cell detachment and death, the triggering events remain obscure. It has been postulated that the binding of pemphigus vulgaris IgG (PVIgG) to KCs induces "desmosomal" signaling. Because in contrast to integrins and classical cadherins, desmoglein (Dsg) molecules are not known to elicit intracellular signaling, and because PV patients also produce non-Dsg autoantibodies, we investigated the roles of both Dsg and non-desmoglein PV antigens. The time course studies of KCs treated with PVIgG demonstrated that the activity of Src peaked at 30 min, EGF receptor kinase (EGFRK) at 60 min, and p38 MAPK at 240 min. The Src inhibitor PP2 decreased EGFRK and p38 activities by ϳ45 and 30%, respectively, indicating that in addition to Src, PVIgG evokes other triggering events. The shrinkage of KCs (cell volume reduction) became significant at 120 min, keratin aggregation at 240 min, and an increase of TUNEL positivity at 360 min. Pretreatment of KCs with PP2 blocked PVIgG-dependent cell shrinkage and keratin aggregation by ϳ50% and TUNEL positivity by ϳ25%. The p38 MAPK inhibitor PD169316 inhibited these effects by ϳ15, 20, and 70%, respectively. Transfection of KCs with small interfering RNAs that silenced expression of Dsg1 and/or Dsg3 proteins, blocked ϳ50% of p38 MAPK activity but did not significantly alter the PVIgG-dependent rise in Src and EGFRK activities. These results indicate that activation of p38 MAPK is a late signaling step associated with collapse of the cytoskeleton and disassembly of desmosomes caused by upstream events involving Src and EGFRK. Therefore, the early acantholytic events are triggered by non-Dsg antibodies.

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“…4,30,[65][66][67][68][69][70] Furthermore, it has been recently reported that inhibitors of tyrosine kinases, phospholipase C, calmodulin, and the serine/threonine kinase protein kinase C prevented PVIgG-induced acantholysis in vivo. 71 TNF-␣ has been shown to activate calpains because of a rise in the concentration of intracellular free Ca 2ϩ . 72 It is well established that TNF-␣ is elevated in the serum of PV patients, [73][74][75][76] deposited in the lesional skin, 77,78 present in the blister fluid, 74 and up-regulated in keratinocytes due to PV antibody binding 78,79 and that anti-TNF-␣ therapy with etanercept (a fusion protein of TNF-␣ receptor) can ameliorate recalcitrant PV.…”

Section: Discussionmentioning

confidence: 99%

Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

Arredondo

Chernyavsky

Karaouni

et al. 2005

The American Journal of Pathology

111

138

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In vivo blockade of pemphigus vulgaris acantholysis by inhibition of intracellular signal transduction cascades

Abstract: These observations strongly support the role of intracellular signalling cascades in the molecular mechanism of PV IgG-induced acantholysis.

Cited by 78 publications

References 30 publications

Pemphigus Vulgaris IgG-induced Desmoglein-3 Endocytosis and Desmosomal Disassembly Are Mediated by a Clathrin- and Dynamin-independent Mechanism

Pemphigus Vulgaris IgG-induced Desmoglein-3 Endocytosis and Desmosomal Disassembly Are Mediated by a Clathrin- and Dynamin-independent Mechanism

Desmoglein Versus Non-desmoglein Signaling in Pemphigus Acantholysis

Novel Mechanisms of Target Cell Death and Survival and of Therapeutic Action of IVIg in Pemphigus

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