An aging-susceptible circadian rhythm controls cutaneous antiviral immunity
Stephen J Kirchner1,2, Vivian Lei1, Paul T Kim1
1Department of Dermatology.
Abstract:
Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced levels of antiviral proteins (AVPs) and circadian regulators, including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin, and such circadian control of AVPs was diminished by disruption of immune cell IL-27 signaling and deletion of Bmal1/Clock genes in mouse skin, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment with the circadian-enhancing agents nobiletin and SR8278 reduced infection of herpes simplex virus 1 in epidermal explants and human keratinocytes in a BMAL1/CLOCK-dependent manner. Circadian-enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations.
Insights
Aging skin
Area of Science:
- Immunology
- Dermatology
- Chronobiology
Background:
- Aged skin exhibits increased susceptibility to viral infections.
- The underlying mechanisms of this immunosenescence-related immune risk are not fully understood.
Purpose of the Study:
- To investigate the role of circadian regulators and antiviral proteins (AVPs) in aged skin's immune response.
- To explore circadian restoration as a potential antiviral strategy for aging populations.
Main Methods:
- Assessed levels of AVPs and circadian regulators (Bmal1, Clock) in aged murine and human skin.
- Investigated the control of rhythmic AVP expression by Bmal1 and Clock.
- Examined the impact of IL-27 signaling disruption and gene deletion/knockdown on circadian AVP regulation.
- Evaluated the efficacy of circadian-enhancing agents (nobiletin, SR8278) against herpes simplex virus 1 infection in skin models.
Main Results:
- Aged skin showed reduced levels of AVPs and circadian regulators Bmal1 and Clock.
- Bmal1 and Clock regulate rhythmic AVP expression, a process impaired by IL-27 signaling disruption and Bmal1/Clock gene alterations.
- Circadian-enhancing treatments effectively reduced viral infection in skin explants and keratinocytes in a BMAL1/CLOCK-dependent manner.
- These treatments reversed the increased susceptibility of aged skin and keratinocytes to viral infections.
Conclusions:
- Cutaneous antiviral immunity is regulated by an evolutionarily conserved, age-sensitive circadian mechanism.
- Restoring circadian function presents a promising antiviral strategy for combating infections in aging individuals.
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