title: Bay11-7082 attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation.
abstract: Nuclear factor-kappa B (NF-κB) and NLRP3 inflammasome are involved in inflammation and autoimmunity. In vitro data have shown that Bay11-7082 selectively inhibits NLRP3 inflammasome activity independent of NF-κB activity. In this study, we evaluated the therapeutic effects of Bay11-7082 on murine lupus nephritis (LN) in vivo. Twelve-week-old MRL/lpr mice were treated with either Bay11-7082 (5mg/kg) or vehicle (DMSO/PBS buffer) by intraperitoneal injection thrice per week for 8 weeks. NLRP3 inflammasome formation and NF-κB activation were measured. Histopathology, immune complex deposits, proteinuria, renal function and production of anti-dsDNA antibody as well as inflammatory markers were evaluated. Bay11-7082 treatment inhibited renal NLRP3 inflammasome formation and NF-κB activation in vivo. Bay11-7082 decreased proteinuria, blood urea nitrogen, resulting in dramatically attenuated renal damage. Bay11-7082-treated mice had decreased serum anti-dsDNA level and less renal immune complex deposition. The IL-1β, TNF-α and chemokine (C-C Motif) ligand 2 (CCL2) levels and infiltration of macrophages as well as the mortality were significantly reduced by Bay11-7082 treatment. This study suggests that dual inhibition of NLRP3 inflammasome and NF-κB activation using Bay11-7082 or its analogues may be a promising therapeutic strategy for preventing the progression of LN.
authors.affiliation: Department of Rheumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China.
authors.forename: Jijun
authors.initials: J
authors.lastname: Zhao
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Yuefang
authors.initials: Y
authors.lastname: Huang
authors.forename: Hongyue
authors.initials: H
authors.lastname: Wang
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhao
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Liang
authors.forename: Niansheng
authors.initials: N
authors.lastname: Yang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D019463:Mice, Inbred MRL lpr; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009570:Nitriles / Q000627:therapeutic use*; D011897:Random Allocation; D013450:Sulfones / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D002352:Carrier Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009570:Nitriles; C492716:Nlrp3 protein, mouse; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha
keywords: Bay11-7082; Lupus nephritis; NF-κB; NLRP3 inflammasome