Inflammasome activation and vitiligo/nonsegmental vitiligo progression

British Journal of Dermatology (Impact Factor: 4.28). 04/2014; 170(4). DOI: 10.1111/bjd.12691


Polymorphisms of NLR (nucleotide-binding domain and leucine rich repeat containing) family, pyrin domain containing protein 1 (NLRP1) have been found in patients with vitiligo/nonsegmental vitiligo (NSV), and increased NLRP1 expression has been detected in the leading edge of lesional skin biopsies.Objectives
To evaluate the presence and intensity of NLRP1 immunostaining in lesional and perilesional skin of patients with vitiligo/NSV and to search for possible correlations between NLRP1 and interleukin (IL)-1β expression, lymphocytic infiltrates and disease activity.Methods
Of 14 consecutive vitiligo/NSV patients, eight had active disease [Vitiligo European Task Force (VETF) spreading score +1 to +5], one patient had stable disease and five patients had regressive disease (VETF spreading score −1 to −3). We performed immunostaining for NLRP1, B and T lymphocytes, IL-1β and kallikrein 7 on lesional and perilesional vitiligo skin.ResultsNLRP1 and IL-1β immunostaining in perilesional vitiligo/NSV skin was significantly associated with progressive disease (P = 0·009 and 0·04, respectively) and performed better than the simple detection of lymphocytic infiltrates.Conclusions
Our findings suggest that markers of the NLRP1 inflammasome could be a useful test for assessing disease activity in addition to the detection of inflammatory infiltrates in the progressing margins of vitiligo/NSV lesions.

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Available from: Muriel Cario-André, Sep 23, 2014
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    • "Ecad staining at the membrane of keratinocytes appeared similar in pigmented areas of vitiligo patients and in healthy controls (Figure 2a). It has been established that IL1b is expressed in all epidermal layers of lesional and perilesional vitiligo skin (Marie et al., 2014). To assess whether altered Ecad in human melanocytes in vivo is associated with the activation of the pro-inflammatory cytokine IL1b, we performed IL1b staining (Supplementary Figure S3a and b online). "
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    ABSTRACT: Vitiligo is the most common depigmenting disorder resulting from the loss of melanocytes from the basal epidermal layer. The pathogenesis of the disease is likely multifactorial and involves autoimmune causes as well as oxidative and mechanical stress. It is important to identify early events in vitiligo, to clarify pathogenesis, improve diagnosis and inform therapy. Here, we show that E-cadherin, which mediates the adhesion between melanocytes and keratinocytes in the epidermis, is absent from, or discontinuously distributed across melanocyte membranes of vitiligo patients long before clinical lesions appear. This abnormality is associated with the detachment of the melanocytes from the basal to suprabasal layers in the epidermis. Using human epidermal reconstructed skin and mouse models with normal or defective E-cadherin expression in melanocytes we demonstrated that E-cadherin is required for melanocyte adhesiveness to the basal layer under oxidative and mechanical stress, establishing a link between silent/pre-clinical, cell-autonomous defects in vitiligo melanocytes and known environmental stressors accelerating disease expression. Our results implicate a primary predisposing skin defect affecting melanocyte adhesiveness, which under stress conditions, leads to disappearance of melanocytes and clinical vitiligo. Melanocyte adhesiveness is thus a potential target for therapy aiming at disease stabilization.Journal of Investigative Dermatology accepted article preview online, 29 January 2015. doi:10.1038/jid.2015.25.
    Full-text · Article · Jan 2015 · Journal of Investigative Dermatology
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    ABSTRACT: Inflammation, a vital response of the immune system to infection and damage to tissues, can be initiated by various germline-encoded innate immune-signaling receptors. Among these, the inflammasomes are critical for activation of the potent proinflammatory interleukin-1 cytokine family. Additionally, inflammasomes can trigger and maintain inflammatory responses aimed toward excess nutrients and the numerous danger signals that appear in a variety of chronic inflammatory diseases. We discuss our understanding of how inflammasomes assemble to trigger caspase-1 activation and subsequent cytokine release, describe how genetic mutations in inflammasome-related genes lead to autoinflammatory syndromes, and review the contribution of inflammasome activation to various pathologies arising from metabolic dysfunction. Insights into the mechanisms that govern inflammasome activation will help in the development of novel therapeutic strategies, not only for managing genetic diseases associated with overactive inflammasomes, but also for treating common metabolic diseases for which effective therapies are currently lacking. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 10 is January 24, 2015. Please see for revised estimates.
    No preview · Article · Nov 2014 · Annual Review of Pathology Mechanisms of Disease
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