p38 MAPK Signaling in Pemphigus: Implications for Skin Autoimmunity

Mavropoulos, Αthanasios; Orfanidou, Timoklia; Liaskos, Christos; Smyk, Daniel S.; Spyrou, Vassiliki; Sakkas, Lazaros I.; Rigopoulou, Eirini I.; Bogdanos, Dimitrios P.

doi:10.1155/2013/728529

Cited by 28 publications

(32 citation statements)

References 116 publications

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“…Indeed, signaling molecules such as, amongst a variety of others, PKC, RhoA, c-Myc and EGFR were demonstrated to participate in the pathogenesis of pemphigus (Spindler et al, 2013;Waschke, 2008;Waschke and Spindler, 2014). Especially, the phosphorylation of p38MAPK appears to be a central mechanism in pemphigus pathogenesis (Mavropoulos et al, 2013), because PV-IgG cause a rapid activation in cultured keratinocytes, mouse models and patients and inhibition of this kinase was protective both in vitro and in vivo (Berkowitz et al, 2008;Berkowitz et al, 2005;Berkowitz et al, 2006;Mao et al, 2014). Mechanistically, p38MAPK activation leads to reorganization of both the actin and intermediate cytoskeleton and to depletion of Dsg3 (Berkowitz et al, 2005;Jolly et al, 2010;Spindler et al, 2013), all of which are known hallmarks of pemphigus pathogenesis (Aoyama and Kitajima, 1999;Oktarina et al, 2011;Spindler et al, 2007;Spindler et al, 2011;Wilgram et al, 1961).…”

Section: Introductionmentioning

confidence: 99%

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Vielmuth

Waschke

Spindler

2015

Journal of Investigative Dermatology

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Pemphigus vulgaris (PV) is a severe autoimmune disease in which autoantibodies against the desmosomal cell adhesion molecules desmoglein (Dsg) 1 and Dsg3 cause intraepidermal blister formation. Mechanistically, the fundamental question is still unresolved whether loss of cell cohesion is a result of (1) direct inhibition of Dsg interaction by autoantibodies or (2) intracellular signaling events, which are altered in response to antibody binding and finally cause desmosome destabilization. We used atomic force microscopy (AFM) to perform Dsg3 adhesion measurements on living keratinocytes to investigate the contributions of direct inhibition and signaling to loss of cell cohesion after autoantibody treatment. Dsg3 binding was rapidly blocked following antibody exposure under conditions where no depletion of surface Dsg3 was detectable, demonstrating direct inhibition of Dsg3 interaction. Inhibition of p38MAPK, a central signaling molecule in PV pathogenesis, abrogated loss of cell cohesion, but had a minor effect on loss of Dsg3 binding. Similarly, the cholesterol-depleting agent methyl-β-cyclodextrin (β-MCD) fully blocked cell dissociation, but did not restore Dsg3 interactions or prevent the activation of p38MAPK. These results demonstrate that inhibition of Dsg3 binding is not sufficient to cause loss of cell cohesion, but rather alters signaling events which, in lipid raft-dependent manner, induce cell dissociation.

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Section: Introductionmentioning

confidence: 99%

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Vielmuth

Waschke

Spindler

2015

Journal of Investigative Dermatology

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“…For example, pemphigus vulgaris is a skin-blistering disease in humans, and enhanced phosphorylation of p38 MAPK is observed in pemphigus vulgaris skin. 51 Human keratinocytes treated with pemphigus vulgaris IgG showed p38 activation and retraction of KIF from the cell membrane. 5 The retraction of KIF was prevented by a p38 MAPK inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

Kawaguchi

Kanemaru

Sawaguchi

et al. 2015

The American Journal of Pathology

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Hepatocyte growth factor activator inhibitor type 1 (HAI-1; official symbol SPINT1) is a membraneassociated serine proteinase inhibitor abundantly expressed in epithelial tissues. Genetically engineered mouse models demonstrated that HAI-1 is critical for epidermal function, possibly through direct and indirect regulation of cell surface proteases, such as matriptase and prostasin. To obtain a better understanding of the role of HAI-1 in maintaining epidermal integrity, we performed ultrastructural analysis of Spint1-deleted mouse epidermis and organotypic culture of an HAI-1 knockdown (KD) human keratinocyte cell line, HaCaT. We found that the aggregation of tonofilaments to desmosomes was significantly reduced in HAI-1edeficient mouse epidermis with decreased desmosome number. Similar findings were observed in HAI-1 KD HaCaT organotypic cultures. Immunoblot and immunohistochemical analyses revealed that p38 mitogen-activated protein kinase was activated in response to HAI-1 insufficiency. Treatment of HAI-1 KD HaCaT cells with a p38 inhibitor abrogated the above-observed ultrastructural abnormalities. The activation of p38 induced by the loss of HAI-1 likely resulted from enhanced signaling of protease-activated receptor-2 (PAR-2), because its silencing abrogated the enhanced activation of p38. Consequently, treatment of HAI-1 KD HaCaT cells with a serine protease inhibitor, aprotinin, or PAR-2 antagonist alleviated the abnormal ultrastructural phenotype in organotypic culture. These results suggest that HAI-1 may have a critical role in maintaining normal keratinocyte morphology through regulation of PAR-2edependent p38 mitogen-activated protein kinase signaling. Human skin protects the body from both water loss and mechanical damage. This barrier function is primarily accomplished by the epidermis, a self-renewing stratified squamous epithelium composed of several layers of keratinocytes. 1 To achieve the barrier functions, keratinocytes form dynamic and strong cell-cell junctions in which desmosomes and the network of keratin intermediate filaments (KIFs) are essential to maintain junctional integrity. 2 KIFs are anchored to the cytoplasm and interact with desmosomal cell-cell contacts at the plasma membrane. These are important for mechanical stability of cell-cell contacts between keratinocytes. 3 Disturbance of the integrity of the KIF network leads to skin-blistering diseases, such as epidermolysis bullosa simplex. 4 Although it is not known how KIF disassembly is regulated, recent studies suggested that p38 mitogen-activated protein kinase (MAPK) signaling is involved in these processes. 4e6 The p38 is a member of the MAPK family. It is present in epithelial cells, responds rapidly to various types of stresses,

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“…Acantholytic mechanisms involving autoantibody-antigen interaction have been reported to directly induce disruption of cell adhesion via intercellular signaling pathways, such as p38 mitogen activated protein kinase (MAPK), heat shock protein 27 (HSP 27), c-myc and epidermal growth factor (EGF)-extracellular signalregulated kinases (ERKs) 1/2 signals (Berkowitz et al, 2008;Getsios et al, 2009). Furthermore, a decrease in DSG-1 epidermal expression has been reported to interfere with DSC-1, keratin 10 and loricrin expression during skin differentiation (Getsios et al, 2009;Mavropoulos et al, 2013). It is known that KIFs retract in acantholytic keratinocytes, which, consequently, leads to the development of PF and pemphigus vulgaris (Bektas et al, 2013;Mavropoulos et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a decrease in DSG-1 epidermal expression has been reported to interfere with DSC-1, keratin 10 and loricrin expression during skin differentiation (Getsios et al, 2009;Mavropoulos et al, 2013). It is known that KIFs retract in acantholytic keratinocytes, which, consequently, leads to the development of PF and pemphigus vulgaris (Bektas et al, 2013;Mavropoulos et al, 2013). Other studies have reported that DSC-1 is a potential auto-antigen in canine PF (Bizikova et al, 2011;; however, reduced DSC-1 expression was found in PE and PPP perhaps because it is possible that subtypes of superficial pemphigus share DSC-1 aberrance as well.…”

Section: Discussionmentioning

confidence: 99%

Expression of keratins, epidermal proteins and inflammatory cells in superficial pemphigus dogs

Theerawatanasirikul¹,

Rungsipipat²,

Banlunara³

et al. 2018

BJVM

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SummaryTheerawatanasirikul, S., A. Rungsipipat, W. Banlunara & P. Pongket, 2018. Expression of keratins, epidermal proteins and inflammatory cells in superficial pemphigus dogs. Bulg. J. Vet. Med., 21, No 2,[186][187][188][189][190][191][192][193][194][195][196][197] Superficial pemphigus in dogs is an autoimmune skin disorder. The disease is characterised by the binding of auto-antibodies to desmosomal molecules including desmocollin-1, a major auto-antigen in dogs. However, data on the expression of epidermal proteins in dogs are still limited. Therefore, the aim of this study was to investigate the keratins and epidermal proteins in dogs with superficial pemphigus using immunohistochemistry. Skin biopsies were performed on dogs with pemphigus foliaceus (n=10), pan-epidermal pustular pemphigus (n=4) and pemphigus erythematosus (n=1). Immunostaining for keratin 5 and keratin 10 showed a premature and discontinuous pattern in the suprabasal layers of all pemphigus skin samples compared to the control group (P<0.05). Filaggrin, desmocollin-1 and claudin-1, but not involucrin, were significantly reduced (P<0.05). Inflammatory cells markedly infiltrated in the dermis and the lower epidermis of all pemphigus skins. This is the first report that associates changes in the expression of keratin 5, keratin 10, filaggrin and claudin-1 with reduced desmocollin-1 expression and subsequent loss of the epidermal barrier in superficial pemphigus.

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p38 MAPK Signaling in Pemphigus: Implications for Skin Autoimmunity

Cited by 28 publications

References 116 publications

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Loss of Desmoglein Binding Is Not Sufficient for Keratinocyte Dissociation in Pemphigus

Hepatocyte Growth Factor Activator Inhibitor Type 1 Maintains the Assembly of Keratin into Desmosomes in Keratinocytes by Regulating Protease-Activated Receptor 2–Dependent p38 Signaling

Expression of keratins, epidermal proteins and inflammatory cells in superficial pemphigus dogs

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