Type-1 cytokines regulate MMP-9 production and E-cadherin disruption to promote melanocyte loss in vitiligo
Nesrine Boukhedouni, … , Julien Seneschal, Katia Boniface
Nesrine Boukhedouni, … , Julien Seneschal, Katia Boniface
Published May 5, 2020
Citation Information: JCI Insight. 2020;5(11):e133772. https://doi.org/10.1172/jci.insight.133772.
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Research Article Dermatology Inflammation

Type-1 cytokines regulate MMP-9 production and E-cadherin disruption to promote melanocyte loss in vitiligo

Abstract

Loss of melanocytes is the pathological hallmark of vitiligo, a chronic inflammatory skin depigmenting disorder induced by exaggerated immune response, including autoreactive CD8 T cells producing high levels of type 1 cytokines. However, the interplay between this inflammatory response and melanocyte disappearance remains to be fully characterized. Here, we demonstrate that vitiligo skin contains a significant proportion of suprabasal melanocytes, associated with disruption of E-cadherin expression, a major protein involved in melanocyte adhesion. This phenomenon is also observed in lesional psoriatic skin. Importantly, apoptotic melanocytes were mainly observed once cells were detached from the basal layer of the epidermis, suggesting that additional mechanism(s) could be involved in melanocyte loss. The type 1 cytokines IFN-γ and TNF-α induce melanocyte detachment through E-cadherin disruption and the release of its soluble form, partly due to MMP-9. The levels of MMP-9 are increased in the skin and sera of patients with vitiligo, and MMP-9 is produced by keratinocytes in response to IFN-γ and TNF-α. Inhibition of MMP-9 or the JAK/STAT signaling pathway prevents melanocyte detachment in vitro and in vivo. Therefore, stabilization of melanocytes in the basal layer of the epidermis by preventing E-cadherin disruption appears promising for the prevention of depigmentation occurring in vitiligo and during chronic skin inflammation.

Authors

Nesrine Boukhedouni, Christina Martins, Anne-Sophie Darrigade, Claire Drullion, Jérôme Rambert, Christine Barrault, Julien Garnier, Clément Jacquemin, Denis Thiolat, Fabienne Lucchese, Franck Morel, Khaled Ezzedine, Alain Taieb, François-Xavier Bernard, Julien Seneschal, Katia Boniface

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Figure 3

MMP-9 levels are increased in patients with vitiligo and correlate with soluble E-cadherin levels and surface of depigmentation.

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MMP-9 levels are increased in patients with vitiligo and correlate with ...
(A) ELISA levels of MMP-9 in the sera of healthy controls (n = 18), patients with stable (n = 37) or active (n = 37) vitiligo, and patients with psoriasis (n = 20). (B) Active MMP-9 levels in the sera of healthy controls (n = 22), patients with stable (n = 30) or active (n = 39) vitiligo, and patients with psoriasis (n = 19). (C) Spearman’s rho correlation (2-tailed) between MMP-9 and soluble E-cadherin levels in the sera of patients with vitiligo (n = 73). (D) Spearman’s rho correlation (2-tailed) between serum active MMP-9 and body surface area (BSA) involved in patients with vitiligo (n = 59). (E) Representative IHC staining of MMP-9 expression in healthy control skin, perilesional skin of stable and active vitiligo, and lesional psoriatic skin. Scale bar: 100μm. (F) Semiquantitative analysis of MMP-9 expression in skin from healthy controls (n = 5), perilesional skin of vitiligo patients with stable (n = 11) or active (n = 10) disease, and lesional psoriatic skin (n = 8). (G and H) Inflammatory transcriptomic profile of perilesional skin of patients with stable (n = 3) and active (n = 6) vitiligo was assessed using NanoString technology. (G) The most upregulated genes are shown. Results show the change in gene expression between the 2 groups. (H) Predicted protein-protein interaction networks for upregulated genes using STRING online tool. The thickness of edges represents the strength of data support. The thicker the edge between 2 proteins, the more these proteins are linked based on the enrichment evidenced by STRING. (I and J) Reconstructed human pigmented epidermis (RHPE), NHEK, and NHEM were stimulated for 24 hours in the absence or presence of TNF-α and IFN-γ. (I) Real-time PCR analysis of MMP9 gene expression in RHPE (n = 7), NHEK (n = 9), and NHEM (n = 7). Data are shown as fold increase above the control culture. GAPDH was used as a housekeeping gene. (J) Levels of MMP-9 in cell-free culture supernatants of RHPE (n = 13, left) and NHEK (n = 9, right). (K) Western blot analysis of MMP-9 expression in NHEK treated for 24 hours in the presence or absence of 20 ng/mL of TNF-α and IFN-γ. Data in A, B, F, I, and J show mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001; calculated with Kruskal-Wallis (A, B, and F) or Wilcoxon tests (I and J).