The role of nitric oxide synthases in pemphigus vulgaris in a mouse model

Marquina, Miren; España, A.; Fernández-Galar, Marta; López-Zabalza, Marı́a J.

doi:10.1111/j.1365-2133.2008.08582.x

Cited by 21 publications

(39 citation statements)

References 59 publications

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“…Also, it has been demonstrated that PV-IgG induces EGFR activation, and EGFR inhibition prevents acantholysis (11,35). These issues are in line with our previous observation that the tyrosinekinase (TK) inhibitor genistein inhibited nNOS expression induced by PV-IgG (28). Here, we observed that PV-IgG increased nNOS expression in a HER isoform-dependent way.…”

Section: Discussionsupporting

confidence: 91%

“…The free radical NO may react with the superoxide anion (O 2 À ) to produce the tissue-damaging agent peroxynitrite, which may rapidly nitrate tyrosine residues in proteins to form nitrotyrosine residues (NTR) (26,27). Our group has previously demonstrated that nNOS plays a relevant role in PV acantholysis using a mouse model (28). Usually, nNOS was expressed in a constitutive form in the basal cells of the epidermis, with increased levels of expression following exposure of the epidermis to PV-IgG.…”

Section: Introductionmentioning

confidence: 98%

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

España

Mòdol

Gil

et al. 2013

Experimental Dermatology

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 98%

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

España

Mòdol

Gil

et al. 2013

Experimental Dermatology

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“…Acantholysis can be blocked both by inhibitors of signaling kinases, such as p38 MAPK (3), mammalian target of rapamycin (4), Src, and epidermal growth factor receptor (EGFR) kinase (2, 4 -7) and by other tyrosine kinases, phospholipase C, calmodulin, and protein kinase C (8,9), as well as inhibitors of executioner caspases (4,10,11). The inhibitors of EGFR, Src, p38 MAPK, and mammalian target of rapamycin, can also abolish PVIgG-dependent activation of the apoptotic pathways in KCs (4,12).…”

Section: Pemphigus Vulgaris (Pv)mentioning

confidence: 99%

“…The serum factors implicated in apoptolysis include Fas ligand (FasL) (14), tumor necrosis factor ␣ (15,16), interleukins 1, 6, 8, and 15 (15,(17)(18)(19), nitric oxide (9,20), kallikreins, and other proteases (21). Using an organ culture model of PV, it has been demonstrated that PVIgG works together with FasL and tumor necrosis factor ␣ to induce apoptolysis (22).…”

Section: Pemphigus Vulgaris (Pv)mentioning

confidence: 99%

Antimitochondrial Autoantibodies in Pemphigus Vulgaris

Marchenko

Chernyavsky

Arredondo

et al. 2010

Journal of Biological Chemistry

115

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A loss of epidermal cohesion in pemphigus vulgaris (PV) results from autoantibody action on keratinocytes (KCs) activating the signaling kinases and executioner caspases that damage KCs, causing their shrinkage, detachment from neighboring cells, and rounding up (apoptolysis). In this study, we found that PV antibody binding leads to activation of epidermal growth factor receptor kinase, Src, p38 MAPK, and JNK in KCs with time pattern variations from patient to patient. Both extrinsic and intrinsic apoptotic pathways were also activated. Although Fas ligand neutralizing antibody could inhibit the former pathway, the mechanism of activation of the latter remained unknown. PV antibodies increased cytochrome c release, suggesting damage to mitochondria. The immunoblotting experiments revealed penetration of PVIgG into the subcellular mitochondrial fraction. The antimitochondrial antibodies from different PV patients recognized distinct combinations of antigens with apparent molecular sizes of 25, 30, 35, 57, 60, and 100 kDa. Antimitochondrial antibodies were pathogenic because their absorption abolished the ability of PVIgG to cause keratinocyte detachment both in vitro and in vivo. The downstream signaling of antimitochondrial antibodies involved JNK and late p38 MAPK activation, whereas the signaling of anti-desmoglein 3 (Dsg3) antibody involved JNK and biphasic p38 MAPK activation. Using KCs grown from Dsg3؊/؊ mice, we determined that Dsg3 did not serve as a surrogate antigen allowing antimitochondrial antibodies to enter KCs. The PVIgG-induced activation of epidermal growth factor receptor and Src was affected neither in Dsg3KCs nor due to absorption of antimitochondrial antibodies. These results demonstrated that apoptolysis in PV is a complex process initiated by at least three classes of autoantibodies directed against desmosomal, mitochondrial, and other keratinocyte self-antigens. These autoantibodies synergize with the proapoptotic serum and tissue factors to trigger both extrinsic and intrinsic pathways of cell death and break the epidermal cohesion, leading to blisters. Further elucidation of the primary signaling events downstream of PV autoantigens will be crucial for the development of a more successful therapy for PV patients.Pemphigus vulgaris (PV) 3 is an IgG autoantibody-mediated disease of skin and mucosa caused by a loss of epidermal cohesion and manifested by progressive blistering and non-healing erosions. The mechanism of detachment of keratinocytes (KCs) in PV, termed acantholysis, is a subject of intensive research. Elucidation of the pathophysiologic mechanism of acantholysis should facilitate development of novel pharmacologic approaches to prevent and treat blistering without systemic corticosteroids, a mainstay of treatment of PV patients. Acantholysis can be blocked both by inhibitors of signaling kinases, such as p38 MAPK (3), mammalian target of rapamycin (4), Src, and epidermal growth factor receptor (EGFR) kinase (2, 4 -7) and by other tyrosine kinases, phospholipase C, calmodulin...

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“…We have observed that iNOS expression is enhanced in patients with pemphigus vulgaris [33] with a role in the pathogenesis of the disease contributing to the increase of inflammation in tissues by the generation of nitrotyrosine residues [34]. The formation of 3-nitrotyrosine in proteins creates new epitopes that can elicit both humoral and cellular immune response.…”

Section: Discussionmentioning

confidence: 98%

Detection of 3-nitrotyrosine-modified human leukocyte antigen–G in biological fluids

2009

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The role of nitric oxide synthases in pemphigus vulgaris in a mouse model

Abstract: SUMMARYBackground: Pemphigus vulgaris (PV) is a blistering autoimmune disease characterized by IgG autoantibodies against desmoglein 3. Nitric oxide synthases (NOS) may contribute to the increase of inflammation in tissues by the generation of nitrotyrosine residues (NTR).

Cited by 21 publications

References 59 publications

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

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

Antimitochondrial Autoantibodies in Pemphigus Vulgaris

Detection of 3-nitrotyrosine-modified human leukocyte antigen–G in biological fluids

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