816 Dual LSD1/HDAC inhibition accelerates skin wound healing

Abstract

Antiviral proteins (AVPs) including the oligoadenylate-synthase (OAS) and Interferon induced transmembrane protein (IFITM) families have protective roles within the innate immune system. However, little is known about their regulation in skin. BMAL1 and CLOCK, regulators of the circadian rhythm, have known importance in a number of immune functions. We hypothesized that the circadian clock may regulate cutaneous AVP expression. We demonstrate that murine skin displays homeostatic oscillations of AVP expression through the day, and that AVPs exhibit modest rhythmic expression in primary human keratinocytes post-circadian synchronization using serum starvation or dexamethasone shock with a periodicity of 20 to 24 hours. siRNA knockdown of CLOCK also decreased AVP expression in vitro. Further in silico analysis revealed that murine and non-human primate skin display circadian expression of AVPs. Notably, we have found that skin wounding at different times of day induces variable AVP expression. Woundinduced transcription of AVPs also was attenuated in ClockD19 circadian mutant mice. These findings support a paradigm where circadian rhythm may control time-of-day anticipatory AVP transcriptional production in order to prioritize cutaneous defenses when the host is more likely to be wounded and encounter pathogens. Further work is needed to establish the mechanistic links of wounding, circadian rhythm, and the AVP response to ultimately permit a better understanding of our skin's homeostatic and wound-induced viral defense mechanisms.