title: BAY 11-7082 inhibits the NF-κB and NLRP3 inflammasome pathways and protects against IMQ-induced psoriasis.
abstract: BAY 11-7082 antagonizes I-κB kinase-β preventing nuclear translocation of nuclear factor-κB (NF-κB); it also inhibits NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation. NF-κB 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 μl/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-κB and NLRP3 activation. BAY 11-7082 blunted epidermal thickness, acanthosis and inflammatory infiltrate. BAY 11-7082 reduced pNF-κB, NLRP3, tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β 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-κB 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-κB and NLRP3.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy.
authors.forename: Natasha
authors.initials: N
authors.lastname: Irrera
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Vaccaro
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pallio
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pizzino
authors.affiliation: Department of Human Pathology, University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Lentini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arcoraci
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Michele
authors.initials: M
authors.lastname: Scuruchi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cutroneo
authors.affiliation: Department of Human Pathology, University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy.
authors.forename: Giuseppe Pio
authors.initials: GP
authors.lastname: Anastasi
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168 Messina, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.affiliation: Department of Biomedical and Dental Sciences and Morphological and Functional Sciences, University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125, Messina, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
mesh_terms: D000634:Aminoquinolines; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics; D003879:Dermatologic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003875:Drug Eruptions / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000077271:Imiquimod; D058847:Inflammasomes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D011565:Psoriasis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000634:Aminoquinolines; D016207:Cytokines; D003879:Dermatologic Agents; D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009570:Nitriles; C492716:Nlrp3 protein, mouse; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D013450:Sulfones; D000077271:Imiquimod
keywords: BAY 11-7082; NOD-like receptor family; nuclear factor-κB (NF-κB); psoriasis-like dermatitis; pyrin domain containing 3 (NLRP3)