The role of NLRP3 inflammasome activation in LC for vitiligo

Patients suffering from vitiligo develop characteristic white, non-scaly skin lesions resulting from loss of pigmentation. This disease affects around 1 percent of the world population and vitiligo patients frequently suffer from other autoimmune diseases like diabetes pointing at genetic predisposition. Above that, the depigmentation affects patients mental health and well- being because of its stigmatizing effect. These depigmented skin areas are caused by an attack of the immune system against the melanin-producing skin cells, called melanocytes. These cells constantly deal with an elevated cellular stress level, due to sun exposure and the energy consuming process of pigment production. But besides these melanocyte-specific defects, the skin immune system is key to the development of vitiligo. The innate immunity can react to danger signals that are released by stressed and damaged melanocytes. Interesting molecules recognizing these danger signals are the Nod-like receptor family member NLRP1 and NLRP3 which were discovered as genetic risk factors for vitiligo. Nowadays vitiligo is classified as an autoimmune disease, in which the innate and adaptive immune system play an important role. As such, stress-related signals released by melanocytes lead to the activation of innate immune cells, partly through NLRP3 or NLRP1. The innate immune system represents the first line of immunological defense and communicates danger to the adaptive immune system. Through this process, T cells are activated and travel to the skin to kill specifically melanocytes. One important cell type acting as a bridge between innate and adaptive immunity are dendritic cells. The skin hosts several types of dendritic cells with the major subset of Langerhans cells residing in the epidermis. Interestingly, Langerhans cells express high levels of NLRP3 and in human vitiligo patients, NLRP1-expressing Langerhans cells have been identified near lesions. Despite these findings and the localization of Langerhans cells next to melanocytes, the role of this important immune cell type for vitiligo pathogenesis is not clear yet. To fill this gap in knowledge, I will investigate the role of Langerhans cells during the onset of vitiligo. We hypothesize that Langerhans cells in the epidermis are crucial guardians for skin homeostasis and that in vitiligo-affected skin, the release of danger signals leads to NLRP3 signaling and Langerhans cell activation, which ultimately kick-starts an autoreactive T cell meditated immune response. Besides this, I will investigate a novel Langerhans cell-targeted therapy approach to exploit the tolerogenic capacities of LC to reinstall tolerance to melanocytes in vitiligo.