Age And Circadian Regulation Of Cutaneous Innate Antiviral Immunity At Homeostasis

Neonates and the elderly are at increased risk for skin viral and bacterial infections that have the potential to cause systemic malaise and death. Innate antiviral proteins (AVPs), a component of the natural antimicrobial defense program, are expressed in the skin and protect the host against potential viral infections. Interestingly, newborns and the elderly have immature diurnal circadian rhythms. Unknown to us is whether and how changes in circadian regulation throughout age alter homeostatic innate antiviral immune responses in the skin. We hypothesize that age-related modulation of the daily circadian rhythm via the Period circadian regulatory axis facilitates transcriptional regulation of innate antiviral host defense molecules in the skin. In silico analysis of murine and non-human primate skin reveals a subset of cutaneous AVPs that display distinct circadian oscillation at homeostasis. Notably, skin from Bmal1-/- mice show reduced antiviral transcription compared to heterozygous littermates, and siRNA knockdown of CLOCK in human keratinocytes leads to reduced basal AVP mRNA expression (p<0.05). Intriguingly, a subset of cutaneous AVP mRNAs are not expressed in neonatal mice, but peak AVP expression induction instead coincides with increased transcript expression of core circadian gene, Per2, in adult mice (p<0.05). Moreover, elderly mice show reduced constitutive AVP transcript (p<0.05) and protein expression compared to adult mice. These findings suggest that variability in AVP expression across age may be due to changes in circadian regulation of keratinocyte innate immune programs. Future studies are directed to investigate whether age and associated changes in circadian regulation similarly impact anticipatory innate immune responses in the setting of wounds.