Modulation of HMGB1 translocation and RAGE/NFκB cascade by quercetin treatment mitigates atopic dermatitis in NC/Nga transgenic mice.
Quercetin, glycosylated form of flavonoid compound, has potent antioxidant and anti-inflammatory properties. In this study, we have investigated the effects of quercetin on skin lesion, high-mobility group box (HMGB)1 cascade signalling and inflammation in atopic dermatitis (AD) mouse model. AD-like lesion was induced by the application of house dust mite extract to the dorsal skin of NC/Nga transgenic mouse. After AD induction, quercetin (50 mg/kg, p.o) was administered daily for 2 weeks. We evaluated dermatitis severity, histopathological changes and changes in protein expression by Western blotting for HMGB1, receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)4, nuclear factor (NF)κB, nuclear factor erythroid-2-related factor (Nrf)2, kelch-like ECH-associated protein (Keap)1, extracellular signal-regulated kinase (ERK)1/2, cyclooxygenase (COX)2, tumor necrosis factor (TNF)α, interleukin (IL)-1β, IL-2Rα and other inflammatory markers in the skin of AD mice. In addition, serum levels of T helper (Th) cytokines (interferon (IFN)γ, IL-4) were measured by enzyme-linked immunosorbent assay. Quercetin treatment attenuated the development of AD-like skin lesions. Histological analysis showed that quercetin inhibited hyperkeratosis, parakeratosis, acanthosis, mast cells and infiltration of inflammatory cells. Furthermore, quercetin treatment downregulated cytoplasmic HMGB1, RAGE, nuclear p-NFκB, p-ERK1/2, COX2, TNFα, IL-1β, IL-2Rα, IFNγ and IL-4 and upregulated nuclear Nrf2. Our data demonstrated that the HMGB1/RAGE/NFκB signalling might play an important role in skin inflammation, and quercetin treatment could be a promising agent for AD by modulating the HMGB1/RAGE/NFκB signalling and induction of Nrf2 protein.
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Vengadeshprabhu
V
Karuppagounder
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Somasundaram
S
Arumugam
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.|Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA.
Rajarajan A
RA
Thandavarayan
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Vigneshwaran
V
Pitchaimani
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Remya
R
Sreedhar
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Rejina
R
Afrin
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Meilei
M
Harima
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Hiroshi
H
Suzuki
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Mayumi
M
Nomoto
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Shizuka
S
Miyashita
Department of Gastroenterology, Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan.
Kenji
K
Suzuki
Department of Cardiology, Yamanashi Prefectural Central Hospital, Kofu-city, Yamanashi, Japan.
Masahiko
M
Nakamura
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Kenichi
K
Watanabe
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D040001:Dermatophagoides farinae / Q000472:pathogenicity; D004195:Disease Models, Animal; D005260:Female; D024243:HMGB1 Protein / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011794:Quercetin / Q000494:pharmacology* / Q000627:therapeutic use; D000067759:Receptor for Advanced Glycation End Products / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012867:Skin / Q000187:drug effects / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014178:Translocation, Genetic / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
D000975:Antioxidants; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D011794:Quercetin
cytokine; high-mobility group box protein 1; nuclear factor kappa B; quercetin; receptor for advanced glycation products