Suzanna Salzer1, Sonja Kresse1, Yoji Hirai1, Sarah Koglin1, Markus Reinholz1, Thomas Ruzicka1, Jürgen Schauber2. 1. Department of Dermatology and Allergy, Ludwig-Maximilian-University, Frauenlobstr. 9-11, Munich 80337, Germany. 2. Department of Dermatology and Allergy, Ludwig-Maximilian-University, Frauenlobstr. 9-11, Munich 80337, Germany. Electronic address: juergen.schauber@med.uni-muenchen.de.
Abstract
BACKGROUND: In patients with rosacea, environmental stressors, especially UVB radiation, trigger disease flares that are characterized by inflammation and vascular hyperactivity. An altered innate immune detection and response system, modulated to a large extent by the aberrant production and processing of human cathelicidin LL-37, is thought to play a central role in disease pathogenesis. OBJECTIVE: To investigate whether the proinflammatory and proangiogenic effects of UV radiation are enhanced in the presence of cathelicidin LL-37. METHODS: Human skin ex vivo and epidermal keratinocytes in vitro were exposed to UVB irradiation. The proinflammatory effects of UVB exposure in the presence and absence of LL-37 were characterized using immunoblot, transfection, qPCR, and a cell-based second messenger assay. ELISA was used to assess cytokine release and the angiogenic potential of endothelial cells was evaluated using an in vitro angiogenesis assay. RESULTS: UVB irradiation triggered the inflammasome-mediated processing and release of IL-1β. LL-37 augmented this UV-induced IL-1β secretion by acting on the P2X7 receptor on keratinocytes. P2X7 receptor activation by UVB and LL-37 resulted in an increase in intracellular calcium concentrations, which enhances inflammasome activation and subsequent IL-1β release. Furthermore, IL-1β and LL-37 worked synergistically to increase the angiogenic potential of endothelial cells. CONCLUSION: Cathelicidin LL-37 modulates the proinflammatory and proangiogenic effects of UV radiation and thereby contributes to enhanced sensitivity to sun exposure in rosacea.
BACKGROUND: In patients with rosacea, environmental stressors, especially UVB radiation, trigger disease flares that are characterized by inflammation and vascular hyperactivity. An altered innate immune detection and response system, modulated to a large extent by the aberrant production and processing of human cathelicidin LL-37, is thought to play a central role in disease pathogenesis. OBJECTIVE: To investigate whether the proinflammatory and proangiogenic effects of UV radiation are enhanced in the presence of cathelicidin LL-37. METHODS:Human skin ex vivo and epidermal keratinocytes in vitro were exposed to UVB irradiation. The proinflammatory effects of UVB exposure in the presence and absence of LL-37 were characterized using immunoblot, transfection, qPCR, and a cell-based second messenger assay. ELISA was used to assess cytokine release and the angiogenic potential of endothelial cells was evaluated using an in vitro angiogenesis assay. RESULTS: UVB irradiation triggered the inflammasome-mediated processing and release of IL-1β. LL-37 augmented this UV-induced IL-1β secretion by acting on the P2X7 receptor on keratinocytes. P2X7 receptor activation by UVB and LL-37 resulted in an increase in intracellular calcium concentrations, which enhances inflammasome activation and subsequent IL-1β release. Furthermore, IL-1β and LL-37 worked synergistically to increase the angiogenic potential of endothelial cells. CONCLUSION: Cathelicidin LL-37 modulates the proinflammatory and proangiogenic effects of UV radiation and thereby contributes to enhanced sensitivity to sun exposure in rosacea.
Authors: Yong Chen; Carlene D Moore; Jennifer Y Zhang; Russell P Hall; Amanda S MacLeod; Wolfgang Liedtke Journal: J Invest Dermatol Date: 2017-04 Impact factor: 8.551