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: Jijun Zhao, Hui Zhang, Yuefang Huang, Hongyue Wang, Shuang Wang, Chunmei Zhao, Yingjie Liang, Niansheng Yang
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 17 Issue 1 Pg. 116-22 (Sep 2013) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 23770281 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• Carrier Proteins
• Ccl2 protein, mouse
• Chemokine CCL2
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nitriles
• Nlrp3 protein, mouse
• Sulfones
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Carrier Proteins (genetics, metabolism)
• Chemokine CCL2 (genetics, metabolism)
• Female
• Gene Expression Regulation (drug effects)
• Inflammation (metabolism)
• Kidney (cytology, pathology)
• Lupus Nephritis (drug therapy)
• Macrophages (drug effects)
• Mice
• Mice, Inbred MRL lpr
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nitriles (therapeutic use)
• Random Allocation
• Sulfones (therapeutic use)
• Tumor Necrosis Factor-alpha (genetics, metabolism)