REV-ERB agonist suppresses IL-17 production in γδT cells and improves psoriatic dermatitis in a mouse model

Wang, Shangyi; Kozai, Mina; Mita, Hironobu; Cai, Zimeng; Masum, Md. Abdul; Ichii, Osamu; Takada, Kouhei; Inaba, Mutsumi

doi:10.1016/j.biopha.2021.112283

Cited by 13 publications

(9 citation statements)

References 39 publications

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“…SR9009, a synthetic REV-ERBα agonist, suppressed γδT17 cells in vitro and in vivo. Topical application of SR9009 reduced the in ammatory symptoms of psoriatic dermatitis in mice [42]. NFIL3 has been reported as the intermediate gene between REV-ERBα and RORγt, thus linking the circadian clock to Th17 cell development.…”

Section: Discussionmentioning

confidence: 99%

LiangxueJiedu Formula improves psoriatic dermatitis by regulating the circadian clock to inhibit IL-17-producing Th17 and γδT cells

Xie

Zhang

Lin

et al. 2023

Preprint

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Background Psoriasis is an immune-mediated inflammatory skin disease. The circadian clock influence immune cells and control the skin’s inflammatory response. In this study, we observed the effect of LiangxueJiedu Formula (LXJDF) on imiquimod-induced per2-knockout mice to explore the mechanism of Chinese medicinal herbs in improving skin inflammation via the circadian clock. Methods The per2−/− mice were randomly divided into the model group, the LXJDF group, and the positive drug group (dexamethasone). The dorsal skin of mice was smeared with imiquimod at 9:00 AM (ZT1), and the corresponding drugs were given at 10:00AM (ZT2) and 10:00 PM (ZT14), respectively. The wild-type (WT) mice were smeared vaseline as the control group. The skin lesions were observed and PASI was performed for six consecutive days. The pathological morphology of the skin was determined by HE and immunofluorescence (Ki67, loricrin, and IL-17A) staining, and the epidermis thickness was measured. The spleen weight and index were calculated, and the splenocyte subtypes and serum cytokine levels were detected by flow cytometry. The serum melatonin levels were detected by ELISA. The gene expressions of inflammatory cytokines in the skin were determined by qPCR. The gene and protein expressions of circadian clock-related genes (CLOCK, BMAL1, REV-ERBα, NFIL3, and RORγt) in the skin were determined by qPCR and western blot. Results LXJDF could significantly improve the psoriasiform skin lesions, including the reduction of PASI, thinning of epidermal thickness, inhibition of keratinocytes proliferation, and parakeratosis at two-time points (ZT2 and ZT14). LXJDF could reduce the spleen weight and index and inhibit the number of Th17 cells, γδT cells, and the serum inflammatory factors levels of IL-17A, IL-17F, TNF-α, IL-22, IL-6. In addition, LXJDF could significantly down-regulate the mRNA expressions of IL-17A, IL-17F, IL-23, and IL-6 in the skin. LXJDF significantly increased the expressions of BMAL1 and REV-ERBα, and decreased NFIL3 and RORγt. Conclusions LXJDF ameliorates psoriatic dermatitis by regulating the circadian clock to inhibit IL-17-producing Th17 and γδT cells.

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Section: Discussionmentioning

confidence: 99%

LiangxueJiedu Formula improves psoriatic dermatitis by regulating the circadian clock to inhibit IL-17-producing Th17 and γδT cells

Xie

Zhang

Lin

et al. 2023

Preprint

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“…These processes finally cause neointimal hyperplasia. 3 Previous reports demonstrated a negative role of NR1D1 in the proliferation and migration of several cell lines, including pulmonary adenoma cells, 21 keratinocytes, 22 and glioblastoma cells. 23 This study further confirmed the negative regulatory role of NR1D1 in proliferation and migration of VSMCs.…”

Section: Discussionmentioning

confidence: 99%

Role of Nuclear receptor subfamily 1 group D member 1 in the proliferation, migration of VSMC and vascular intimal hyperplasia

Wang¹,

Qiu²,

Pan³

et al. 2023

Journal of Cardiovascular Pharmacology

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Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) cause neointimal hyperplasia after percutaneous vascular interventions. Nuclear receptor subfamily 1 group D member 1 (NR1D1), a crucial member of circadian clock, is involved in the regulation of atherosclerosis and cellular proliferation. However, whether NR1D1 affects vascular neointimal hyperplasia remains unclear. In this study, we found that activating NR1D1 reduced injury-induced vascular neointimal hyperplasia. Overexpression of NR1D1 reduced the number of Ki-67-positive VSMCs and migrated VSMCs after platelet-derived growth factor (PDGF)-BB treatment. Mechanistically, NR1D1 suppressed the phosphorylation of AKT and 2 main effectors of the mammalian target of rapamycin complex 1 (mTORC1), S6, and 4EBP1 in PDGF-BB-challenged VSMCs. Re-activation of mTORC1 by Tuberous sclerosis 1 siRNA (siTsc1) and re-activation of AKT by SC-79 abolished NR1D1-mediated inhibitory effects on proliferation and migration of VSMCs. Moreover, decreased mTORC1 activity induced by NR1D1 was also reversed by SC-79. Simultaneously, Tsc1 knockdown abolished the vascular protective effects of NR1D1 in vivo. In conclusion, NR1D1 reduces vascular neointimal hyperplasia by suppressing proliferation and migration of VSMCs in an AKT/mTORC1-dependent manner.

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“…Furthermore, treatment with REV-ERBα agonist SR9009 could suppress the inflammatory effects in rheumatoid arthritis [ 30 ]. SR9009 can repress the γδT17 cells and attenuate the inflammatory symptoms, even when applied topically in the psoriasiform model [ 49 ]. REV-ERBs are negative regulators of BMAL1; hence, the repression of rev-erbα can positively affect the expression of bmal1 , as can be seen with the TNFα modulation ( Figure 3 G) [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Expression Patterns of Clock Gene mRNAs and Clock Proteins in Human Psoriatic Skin Samples

Németh

Horváth

Kinyó

et al. 2021

IJMS

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Psoriasis is a systemic inflammatory skin disorder that can be associated with sleep disturbance and negatively influence the daily rhythm. The link between the pathomechanism of psoriasis and the circadian rhythm has been suggested by several previous studies. However, there are insufficient data on altered clock mechanisms in psoriasis to prove these theories. Therefore, we investigated the expression of the core clock genes in human psoriatic lesional and non-lesional skin and in human adult low calcium temperature (HaCaT) keratinocytes after stimulation with pro-inflammatory cytokines. Furthermore, we examined the clock proteins in skin biopsies from psoriatic patients by immunohistochemistry. We found that the clock gene transcripts were elevated in psoriatic lesions, especially in non-lesional psoriatic areas, except for rev-erbα, which was consistently downregulated in the psoriatic samples. In addition, the REV-ERBα protein showed a different epidermal distribution in non-lesional skin than in healthy skin. In cytokine-treated HaCaT cells, changes in the amplitude of the bmal1, cry1, rev-erbα and per1 mRNA oscillation were observed, especially after TNFα stimulation. In conclusion, in our study a perturbation of clock gene transcripts was observed in uninvolved and lesional psoriatic areas compared to healthy skin. These alterations may serve as therapeutic targets and facilitate the development of chronotherapeutic strategies in the future.

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REV-ERB agonist suppresses IL-17 production in γδT cells and improves psoriatic dermatitis in a mouse model

Cited by 13 publications

References 39 publications

LiangxueJiedu Formula improves psoriatic dermatitis by regulating the circadian clock to inhibit IL-17-producing Th17 and γδT cells

LiangxueJiedu Formula improves psoriatic dermatitis by regulating the circadian clock to inhibit IL-17-producing Th17 and γδT cells

Role of Nuclear receptor subfamily 1 group D member 1 in the proliferation, migration of VSMC and vascular intimal hyperplasia

Expression Patterns of Clock Gene mRNAs and Clock Proteins in Human Psoriatic Skin Samples

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