An aging-susceptible circadian rhythm controls cutaneous antiviral immunity
Stephen J. Kirchner, Vivian Lei, Paul T. Kim, Meera Patel, Jessica L. Shannon, David Corcoran, Dalton Hughes, Diana K. Waters, Kafui Dzirasa, Detlev Erdmann, Jörn Coers, Amanda S. MacLeod, Jennifer Y. Zhang
Stephen J. Kirchner, Vivian Lei, Paul T. Kim, Meera Patel, Jessica L. Shannon, David Corcoran, Dalton Hughes, Diana K. Waters, Kafui Dzirasa, Detlev Erdmann, Jörn Coers, Amanda S. MacLeod, Jennifer Y. Zhang
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Research Article Aging Dermatology

An aging-susceptible circadian rhythm controls cutaneous antiviral immunity

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.

Authors

Stephen J. Kirchner, Vivian Lei, Paul T. Kim, Meera Patel, Jessica L. Shannon, David Corcoran, Dalton Hughes, Diana K. Waters, Kafui Dzirasa, Detlev Erdmann, Jörn Coers, Amanda S. MacLeod, Jennifer Y. Zhang

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Figure 6

Antiviral immune decline of aging skin can be rescued by a circadian enhancer treatment.

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Antiviral immune decline of aging skin can be rescued by a circadian enh...
(A) qRT-PCR of Oas1a, Oas2, and Ifitm1 in Bmal1+/– and WT skin that was wounded and collected 24 hours later (n = 3–6 mice/genotype). P value was obtained with 2-way ANOVA with multiple comparisons. (B) qPCR of HSV-1 UL29 gene relative to murine Krt14 in HSV-1–infected aging (>365 days) and young (2–6 months) mouse epidermis (n = 3 skin explants per group). (C) qPCR of viral UL29 relative to murine Krt14 in HSV-1 infection of aging mouse (>365 days) epidermis treated with vehicle or 10 μM SR8278 (n = 3 skin explants per condition). (D and E) qPCR of HSV-1 UL29 in cell culture–conditioned medium of infected P2 and P8 keratinocytes treated with vehicle or 10 μM SR8278 (MOI, 0.01). Graphs represent averages of relative HSV-1 UL29 DNA normalized to Krt14 ± SEM. n = 3/group. (F) Working model of aging-associated decline of cutaneous innate antiviral immunity. Circadian rhythm factors BMAL1 and CLOCK regulate expression of cutaneous AVPs through both keratinocyte-autonomous and leukocyte-mediated processes. IL-27 conveys a time-of-day response and type I IFN signaling ensures a robust antiviral immunity. Aging-associated circadian decline decreases cutaneous antiviral immunity, whereas pharmacological means of circadian enhancement increases it. Except for A, P values reported in this figure were obtained via 2-tailed Student’s t test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. NW, nonwounded skin; W, wounded skin.