620 Inflammasome activation in human keratinocytes and mouse epidermis by ultraviolet radiation

Ultraviolet B radiation (UVB) is a ubiquitous environmental toxin that causes extensive skin damage resulting in inflammation, photoaging and cancer. UVB known to induce inflammasome activation sterile inflammation associated with cytokine release (e.g. IL-1β, IL-18) immune cell infiltration. We developed circularly permutated luciferase reporters for caspase-1 assess by vitro vivo. HaCaT keratinocytes transduced encoding either the caspase-7 or Gasdermin D cleavage sequence became active after exposure UVB, maximum 9 hours post-UVB 15 mJ/cm2. UVB-induced was inhibited pan-caspase inhibitor zVAD (p=0.0002) multi-kinase Dabrafenib (p=0.002), but not pyroptotic pore blocker LaCl3, reactive species scavenger N-acetylcysteine, intracellular calcium chelator BAPTA-AM. Transfection of Poly I:C induced (>80-fold) resulted morphological death, consistent ability toll-like receptor trigger pyroptosis. To evaluate if can vivo, transgenic mice expressing reporter were exposed 50-75 mJ/cm2 assessed bioluminescence. Caspase-1 observed at 6 exposure, returned baseline 24 hours. This data surprising given mouse are reported express proteins activate inflammasomes, influx cells into peaks 24-72 exposure. Thus, mechanism unclear. Since considered be significant driver tissue cancer formation, understanding how activates inflammasomes both acute chronic scenarios will provide opportunities circumvent detrimental photobiology ensues.