Resveratrol Protects against Skin Inflammation through Inhibition of Mast Cell, Sphingosine Kinase-1, Stat3 and NF-κB p65 Signaling Activation in Mice

Abstract

Inflammation is pathogenic to skin diseases, including atopic dermatitis (AD) and eczema. Treatment for AD remains mostly symptomatic with newer but costly options, tainted with adverse side effects. There is an unmet need for safe therapeutic and preventative strategies for AD. Resveratrol (R) is a natural compound known for its anti-inflammatory properties. However, animal and human R studies have yielded contrasting results. Mast cells (MCs) are innate immune skin-resident cells that initiate the development of inflammation and progression to overt disease. R’s effects on MCs are also controversial. Using a human-like mouse model of AD development consisting of a single topical application of antigen ovalbumin (O) for 7 days, we previously established that the activation of MCs by a bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) initiated substantial skin remodeling compared to controls. Here, we show that daily R application normalized O-mediated epidermal thickening, ameliorated cell infiltration, and inhibited skin MC activation and chemokine expression. We unraveled R’s multiple mechanisms of action, including decreased activation of the S1P-producing enzyme, sphingosine kinase 1 (SphK1), and of transcription factors Signal Transducer and Activator of Transcription 3 (Stat3) and NF-κBp65, involved in chemokine production. Thus, R may be poised for protection against MC-driven pathogenic skin inflammation.

Bifidobacterium longum subsp. infantis B6MNI Alleviates Collagen-Induced Arthritis in Rats via Regulating 5-HIAA and Pim-1/JAK/STAT3 Inflammation Pathways

“…39 Activated STAT3 protein then regulates the expression and phosphorylation of downstream genes, such as NF-κB, thus affecting the development of joint inflammation. 40 This corresponds to our research results. B. longum subsp.…”

“…At this point, STAT3 protein, containing the SH2 domain, is recruited, and JAK catalyzes its phosphorylation . Activated STAT3 protein then regulates the expression and phosphorylation of downstream genes, such as NF-κB, thus affecting the development of joint inflammation . This corresponds to our research results.…”

Induction of Semaphorin 3A by Resveratrol and Pinostilbene via Activation of the AHR-NRF2 Axis in Human Keratinocytes

“…While the therapeutic effect of resveratrol on AD has been shown, the mechanism by which it alleviates AD is still unclear. It has been reported that resveratrol suppresses the activation of NF-κBp65 [ 44 ], Janus kinase (JAK) 1 [ 45 ], signal transducer and activator of transcription 3 (Stat3) [ 46 ], and sphingosine kinase 1 [ 46 ], resulting in the downregulation of inflammatory cytokines. However, the possibility that resveratrol acts on AHR and NRF2 to improve the pathogenesis of AD, as shown by this study, has not been reported.…”

Mast Cells in Human Health and Diseases 2.0

“…Chronic inflammation is a common mediator of various disorders, which include many pathological conditions, pain, migraine, depression, anxiety, autoimmune diseases, and fibromyalgia, as well as Alzheimer’s disease, multiple sclerosis, atherosclerosis, cardiovascular diseases, and skin diseases, such as eczema and atopic dermatitis [ 25 , 26 ].…”

“…It has been suggested that the stabilization of MCs as well as the control of cytokine release, for example using natural substances, such as resveratrol or probiotics, may constitute valid and promising therapeutic tools [ 3 , 26 , 30 , 33 ].…”