BAY 11-7082 antagonizes I-kappa B kinase-beta preventing nuclear translocation of nuclear factor-kappa B (NF-kappa B); it also inhibits NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation. NF-kappa B is involved in psoriasis, whereas the role of NLRP3 is controversial. We investigated BAY 11-7082 effects in an experimental model of psoriasis-like dermatitis. Psoriasis-like lesions were induced by a topical application of imiquimod (IMQ) cream (62.5 mg/day) on the shaved back skin of C57BL/6 and NLRP3 knockout (KO) mice for 7 consecutive days. Sham psoriasis animals were challenged with Vaseline cream. Sham and IMQ animals were randomized to receive BAY 11-7082 (20 mg/kg/i. p.) or its vehicle (100 mu l/i. p of 0.9% NaCl). Skin of IMQ animals developed erythema, scales, thickening and epidermal acanthosis. IMQ skin samples showed increased expression of pNF-kappa B and NLRP3 activation. BAY 11-7082 blunted epidermal thickness, acanthosis and inflammatory infiltrate. BAY 11-7082 reduced pNF-kappa B, NLRP3, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1 beta expression, blunted the phosphorylation of signal transducer and activators of transcription 3 (STAT3) and decreased IL-23 levels. In addition, BAY 11-7082 reawakened the apoptotic machinery. NLRP3 KO animals showed a reduced total histological score but persistent mild acanthosis, dermal thickness and expression of pNF-kappa B and pSTAT3, following IMQ application. Our data suggest that BAY 11-7082 might represent an interesting approach for the management of psoriasis-like dermatitis depending on the dual inhibition of NF-kappa B and NLRP3

BAY 11-7082 inhibits the NF-κB and NLRP3 inflammasome pathways and protects against IMQ-induced psoriasis

IRRERA, NATASHA
Co-primo
;
VACCARO, Mario
Co-primo
;
BITTO, ALESSANDRA
Co-primo
;
PALLIO, GIOVANNI
Co-primo
;
PIZZINO, CARMELO GABRIELE
Co-primo
;
LENTINI, Maria;ARCORACI, Vincenzo;MINUTOLI, Letteria;SCURUCHI, MICHELE;CUTRONEO, Giuseppina;ANASTASI, Giuseppe Pio;ETTARI, Roberta;SQUADRITO, Francesco
;
ALTAVILLA, Domenica
Ultimo
2017

Abstract

BAY 11-7082 antagonizes I-kappa B kinase-beta preventing nuclear translocation of nuclear factor-kappa B (NF-kappa B); it also inhibits NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation. NF-kappa B is involved in psoriasis, whereas the role of NLRP3 is controversial. We investigated BAY 11-7082 effects in an experimental model of psoriasis-like dermatitis. Psoriasis-like lesions were induced by a topical application of imiquimod (IMQ) cream (62.5 mg/day) on the shaved back skin of C57BL/6 and NLRP3 knockout (KO) mice for 7 consecutive days. Sham psoriasis animals were challenged with Vaseline cream. Sham and IMQ animals were randomized to receive BAY 11-7082 (20 mg/kg/i. p.) or its vehicle (100 mu l/i. p of 0.9% NaCl). Skin of IMQ animals developed erythema, scales, thickening and epidermal acanthosis. IMQ skin samples showed increased expression of pNF-kappa B and NLRP3 activation. BAY 11-7082 blunted epidermal thickness, acanthosis and inflammatory infiltrate. BAY 11-7082 reduced pNF-kappa B, NLRP3, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1 beta expression, blunted the phosphorylation of signal transducer and activators of transcription 3 (STAT3) and decreased IL-23 levels. In addition, BAY 11-7082 reawakened the apoptotic machinery. NLRP3 KO animals showed a reduced total histological score but persistent mild acanthosis, dermal thickness and expression of pNF-kappa B and pSTAT3, following IMQ application. Our data suggest that BAY 11-7082 might represent an interesting approach for the management of psoriasis-like dermatitis depending on the dual inhibition of NF-kappa B and NLRP3
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11570/3106853
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