Sol, Stefano (2020) Molecular_mechanisms_underlying_epidermal_defects_and_inflammation_in_AEC_syndrome. [Tesi di dottorato]

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AEC syndrome (OMIM #106260) is a severe genetic disorder caused by mutation in the p63 gene, encoding a master regulator of epidermis. AEC syndrome is characterized by congenital erythroderma and severe skin erosions that severe affect the quality of life of patients and are life-threatening. We generated a conditional knock-in mouse model carrying an inducible AEC mutant in p63 (L514F), which similarly exhibits focal skin erosions, reduced resilience to mechanical stress and premature death. At the molecular level, reduced mechanical stress resilience is accompanied with a progressive skin inflammation. Clear signs of severe inflammation are preceded by strongly elevated levels of Thymic stromal lymphopoietin (Tslp), an IL-7 like cytokine. The epidermal-derived Tslp is released in the blood circulation, causing a dramatic expansion of immature B-cells in the bone marrow and giving rise to an autoimmune lymphoproliferative disorder. Genetic ablation of Tslp in the epidermis significantly reduces skin inflammation and increases body weight and survival in AEC mutant mice. In AEC epidermis Tslp induction is accompanied by strong upregulation of the Klk6 protease, whose gene is directly repressed by functional p63. Klk6 treatment or overexpression of its effector NFAT induce Tslp in keratinocytes. In vitro co-treatment of primary keratinocytes with an active form of recombinant human Klk6 and a combination of inhibitors of NFAT- and NF-κB signaling show a significant reduction of Tslp expression level. Collectively these data indicate that extensive skin erosions in AEC syndrome can cause systemic inflammation and an autoimmune lymphoproliferative disorder due to excessive Tslp production, and point to novel therapeutic targets for AEC syndrome. In addition, it has recently demonstrated that AEC syndrome is a protein aggregation disorder as AEC-associated p63 mutations lead to protein misfolding, aggregation and impairment of transcriptional activity. Based on this knowledge, I tested potential therapeutic approaches to treat AEC syndrome based on preventing aggregation and/or enforcing the endogenous protein disaggregation machinery either by an unbiased high-throughput screening of small molecules that may be able to restore the correct folding of the mutant protein or by genetic manipulations of specific chaperons.

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