An aging-susceptible circadian rhythm controls cutaneous antiviral immunity
Stephen J. Kirchner, … , Amanda S. MacLeod, Jennifer Y. Zhang
Stephen J. Kirchner, … , Amanda S. MacLeod, Jennifer Y. Zhang
Published September 19, 2023
Citation Information: JCI Insight. 2023;8(20):e171548. https://doi.org/10.1172/jci.insight.171548.
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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 1

Aging skin exhibits diminished circadian, AVP, and IL-27 transcription.

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Aging skin exhibits diminished circadian, AVP, and IL-27 transcription. ...
(A) Quantitative PCR (qPCR) of Bmal1, Clock, and Per2 in aged (n = 14–16, >1 year old) and young (n = 32–34 1 month old) male murine skin. Graphs represent averages of relative mRNA ± SEM with GAPDH used for an internal control. P values were obtained via 2-tailed Student’s t test. (B) qPCR of BMAL1, PER2, and IFITM1 in human primary keratinocytes over serial passaging (n = 2–3 donors/passage). Graphs represent averages of relative mRNA ± SEM with GAPDH used for an internal control. (C) qRT-PCR of Oas1, Oas2, and Ifitm1 in aged and young murine back skins as described in A. P values were obtained via 2-tailed Student’s t test. (D) Immunostaining for OAS1a (orange) and nuclei (blue) in aged and young nonwounded skin. Scale bar: 25 μm. (E) qRT-PCR of AVP in young and old skin 24 hours after wounding. Graphs represent averages of relative mRNA ± SEM with GAPDH used for an internal control. P values were obtained via 2-way ANOVA with multiple comparison. NW, nonwounded skin; W, wounded skin. (F) Immunostaining for CD301b (green) and nuclei (blue) in aged and young unwounded skin. Scale bar: 25 μm. (G) Flow cytometry showing reduced numbers of CD301b+ cells in aged skin compared with young skin (n = 4 mice/group) as a percentage of total harvested live, single cells. P values were obtained via 2-way ANOVA with multiple comparisons. (H) Histogram displays IL-27 production from CD11b+ (yellow) and CD301b+ (blue) cells compared with CD45– (red). The flow cytometry gating strategy is included in Supplemental Figure 1. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.