1225 Paving the road to explain melanocyte loss in vitiligo: An uncovered role of matrix metalloprotease MMP9

Abstract

Melanocyte loss is the pathological hallmark of vitiligo, the archetype of a chronic depigmenting inflammatory skin disorder. Yet, whether such disappearance results from melanocyte death and/or detachment is still a matter of debate. We previously showed that vitiligo skin is imprinted with resident memory T cells producing elevated levels of IFNγ and TNFα, while displaying moderate cytotoxicity. Therefore, we investigated the interplay between the inflammatory response characterizing vitiligo disease and melanocyte loss. We found that the combined activity of IFNγ and TNFα induced melanocyte detachment rather than their death in reconstructed pigmented human epidermis through defect of E-cadherin expression, the major protein involved in melanocyte attachment to keratinocytes, and the release of soluble E-cadherin. Such phenomenon was undeniably observed in vitiligo patients skin and was further confirmed in vivo following dermal injection of both IFNγ and TNFα. Additional experiments demonstrated that these two cytokines induced the production of active matrix metalloproteinase 9 (MMP9) by keratinocytes, leading to the cleavage of E-cadherin and instability of melanocytes. MMP9 levels were found increased in vitiligo skin and patients sera and positively correlated with the body surface area involved. Lastly, we showed that MMP9 inhibition downregulated melanocyte detachment in vitro and in vivo. These results emphasize a new mechanism to explain depigmentation associated with inflammation and highlight MMP9 as a new therapeutic target in vitiligo, a disease that still suffers from a lack of effective treatment.