166 Kindlin-1 protects keratinocytes against UV-B: Prospects for antioxidant treatment in Kindler syndrome

Abstract

Kindler syndrome (KS) is an autosomal recessive condition comprising skin fragility and photosensitivity, for which no cure is available yet. It is caused by mutations leading to deficiency of kindlin-1, a protein of ß1 integrin associated adhesions. In KS patients short and long-term effects of sun exposure significantly contribute to morbidity. Here, we unraveled molecular mechanisms of increased sensitivity to UV-B of kindlin-1 deficient keratinocytes from KS patients. We demonstrate a direct relationship between kindlin-1 abundance and UV-B induced apoptosis of keratinocytes and show that low levels of kindlin-1 relieve this feature. Activation of the stress inducible MAPK p38 is significantly increased in kindlin-1 deficient keratinocytes and points to a role of kindlin-1 as a protector against stressors. UV-B accounts for additional augmentation of cellular responses - p38 activation and upregulation of pro inflammatory cytokines like TNF-α - which further launch the regulation of downstream factors controlling multiple cellular processes, including autocrine and paracrine effects. Our results are relevant for translational approaches. Inhibition of p38 activation and TNF-α signaling effectively reduced UV-B induced apoptosis in monolayer keratinocyte cultures and in organotypic cocultures. Besides these, we show that antioxidants, and in particular the plant flavonoid luteolin, represent feasible topical therapeutic approaches. Both substances as well as the skin cream Protexsan (0.1% luteolin, 0.1% vitamin E, 0.025% ubiquinone) significantly decreased UV-B induced apoptosis in monolayer KS keratinocyte cultures and in organotypic cocultures. These new insights provide evidence for antioxidants as therapeutic approaches to alleviate the progressive course of KS.