Cathelicidin peptide LL-37 increases UVB-triggered inflammasome activation: Possible implications for rosacea

• UVB triggers inflammasome mediated IL-1β release by keratinocytes.
• LL-37 enhances UV-induced IL-1β secretion by acting on the P2X7 receptor.
• P2X7 receptor activation results in an increase in intracellular calcium concentrations.
• IL-1β and LL-37 work synergistically to promote angiogenesis.
• LL-37 augments the proinflammatory and proangiogenic effects of UVB.

BackgroundIn 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.ObjectiveTo investigate whether the proinflammatory and proangiogenic effects of UV radiation are enhanced in the presence of cathelicidin LL-37.MethodsHuman 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.ResultsUVB 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.ConclusionCathelicidin LL-37 modulates the proinflammatory and proangiogenic effects of UV radiation and thereby contributes to enhanced sensitivity to sun exposure in rosacea.