Circadian control of interferon-sensitive gene expression in murine skin

Greenberg, Elyse Noelani; Marshall, Michaela; Jin, Suoqin; Venkatesh, Sanan; Dragan, Morgan; Tsoi, Lam C.; Guðjónsson, Jóhann E.; Nie, Qing; Takahashi, Joseph S.; Andersen, Bogi

doi:10.1073/pnas.1915773117

Cited by 43 publications

(67 citation statements)

References 48 publications

(56 reference statements)

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“…The results revealed that CDK1 protein was overexpressed (positively intense stained) in psoriatic skin lesions as compared to non-lesional areas. This observation was consistent with that in the study by Greenberg et al (2020) ( 63 ), who reported an increased CDK1 expression in psoriatic lesions. The psoriasis skin lesions and non-lesional skins were assessed for the expression and localization of CDH1.…”

Section: Discussionsupporting

confidence: 93%

Transcriptomic landscaping of core genes and pathways of mild and severe psoriasis vulgaris

et al. 2020

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Psoriasis is a common chronic inflammatory skin disease affecting >125 million individuals worldwide. The therapeutic course for the disease is generally designed upon the severity of the disease. In the present study, the gene expression profile GSE78097, was retrieved from the National Centre of Biotechnology (NCBI)-Gene Expression Omnibus (GEO) database to explore the differentially expressed genes (DEGs) in mild and severe psoriasis using the Affy package in R software. The Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways of the DEGs were analysed using clusterProfiler, Bioconductor, version 3.8. In addition, the STRING database was used to develop DEG-encoded proteins and a protein-protein interaction network (PPI). Cytoscape software, version 3.7.1 was utilized to construct a protein interaction association network and analyse the interaction of the candidate DEGs encoding proteins in psoriasis. The top 2 hub genes in Cytohubba plugin parameters were validated using immunohistochemical analysis in psoriasis tissues. A total of 382 and 3,001 dysregulated mild and severe psoriasis DEGs were reported, respectively. The dysregulated mild psoriasis genes were enriched in pathways involving cytokine-cytokine receptor interaction and rheumatoid arthritis, whereas cytokine-cytokine receptor interaction, cell cycle and cell adhesion molecules were the most enriched pathways in severe psoriasis group. PL1N1, TLR4, ADIPOQ, CXCL8, PDK4, CXCL1, CXCL5, LPL, AGT, LEP were hub genes in mild psoriasis, whereas BUB1, CCNB1, CCNA2, CDK1, CDH1, VEGFA, PLK1, CDC42, CCND1 and CXCL8 were reported hub genes in severe psoriasis. Among these, CDC42, for the first time (to the best of our knowledge), has been reported in the psoriasis transcriptome, with its involvement in the adaptive immune pathway. Furthermore, the immunoexpression of CDK1 and CDH1 proteins in psoriasis skin lesions were demonstrated using immunohistochemical analysis. On the whole, the findings of the present integrated bioinformatics and immunohistochemical study, may enhance our under-standing of the molecular events occurring in psoriasis, and these candidate genes and pathways together may prove to be therapeutic targets for psoriasis vulgaris.

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Section: Discussionsupporting

confidence: 93%

Transcriptomic landscaping of core genes and pathways of mild and severe psoriasis vulgaris

et al. 2020

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“…This suggested to us that an unknown, non-canonical pathway from IFN-γ to the clock was active. During the revision of this manuscript, a study provided evidence that imiquimod, through TLR7, triggers IFN regulatory factor 7 (Irf7) in mouse skin and also suppresses several core clock genes (65). Given that multiple pro-inflammatory stimuli were able to suppress PER2 LUC , it is tantalizing to speculate that there may be a common player, such as Irf7, related to all of these stimuli.…”

Section: Discussionmentioning

confidence: 99%

A Pro- and Anti-inflammatory Axis Modulates the Macrophage Circadian Clock

et al. 2020

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The circadian clock broadly governs immune cell function, leading to time-of-day differences in inflammatory responses and subsequently, pathogen clearance. However, the effect of inflammatory signals on circadian machinery is poorly understood. We found that in bone marrow-derived macrophages, some host-derived pro-inflammatory cytokines, e.g., IFN-γ or TNF-α, and pathogen-associated molecular patterns, e.g., LPS or Pam3Csk4, suppress the amplitude in oscillations of circadian negative feedback arm clock components such as PER2, and when examined, specific combinations of these immune-related signals suppressed the amplitude of these oscillations to a greater degree in both bone marrow-derived and peritoneal macrophages. At the transcript level, multiple components of the circadian clock were affected in different ways by pro-inflammatory stimulus, including Per2 and Nr1d1. This suppressive effect on PER2 did not arise from nor correlate with cell death or clock resetting. Suppression of the clock by IFN-γ was dependent on its cognate receptor; however, pharmacological inhibition of the canonical JAK/STAT and MEK pathways did not hinder suppression, suggesting a mechanism involving a non-canonical pathway. In contrast, anti-inflammatory signals such as IL-4 and dexamethasone enhanced the expression of PER2 protein and Per2 mRNA. Our results suggest that the circadian system in macrophages can differentially respond to pro-and anti-inflammatory signals in their microenvironments.

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“…Indeed, the disruption of circadian rhythms has been suggested to lead to the impairment of innate immunity 26 - 28 . In particular, mice lacking circadian rhythms showed robust activation of the IFN pathway 27 , and the circadian clock has been shown to regulate cellular susceptibility to the herpes and influenza viruses 29 . A recent study revealed that systemic Bmal1-knockout (KO) mice had an exacerbated imiquimod-induced ISG response in the skin and isolated epidermis, suggesting an involvement of the circadian clock in the innate antiviral response 27 .…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 infection activates a subset of intrinsic pathways to inhibit type I interferons in vitro and in vivo

et al. 2021

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SARS-CoV-2 infection poses a global challenge to human health. Upon viral infection, host cells initiate the innate antiviral response, which primarily involves type I interferons (I-IFNs), to enable rapid elimination of the invading virus. Previous studies revealed that SARS-CoV-2 infection limits the expression of I-IFNs in vitro and in vivo , but the underlying mechanism remains incompletely elucidated. In the present study, we performed data mining and longitudinal data analysis using SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells and ferrets, and the results confirmed the strong inhibitory effect of SARS-CoV-2 on the induction of I-IFNs. Moreover, we identified genes that are negatively correlated with IFNB1 expression in vitro and in vivo based on Pearson correlation analysis. We found that SARS-CoV-2 activates numerous intrinsic pathways, such as the circadian rhythm, phosphatidylinositol signaling system, peroxisome, and TNF signaling pathways, to inhibit I-IFNs. These intrinsic inhibitory pathways jointly facilitate the successful immune evasion of SARS-CoV-2. Our study elucidates the underlying mechanism by which SARS-CoV-2 evades the host innate antiviral response in vitro and in vivo , providing theoretical evidence for targeting these immune evasion-associated pathways to combat SARS-CoV-2 infection.

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Circadian control of interferon-sensitive gene expression in murine skin

Cited by 43 publications

References 48 publications

Transcriptomic landscaping of core genes and pathways of mild and severe psoriasis vulgaris

Transcriptomic landscaping of core genes and pathways of mild and severe psoriasis vulgaris

A Pro- and Anti-inflammatory Axis Modulates the Macrophage Circadian Clock

SARS-CoV-2 infection activates a subset of intrinsic pathways to inhibit type I interferons in vitro and in vivo

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