Pharmacological targeting of NLRP3 deubiquitination for treatment of NLRP3-associated inflammatory diseases.

Abstract

Pharmacologically inhibiting nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome activation results in potent therapeutic effects in a wide variety of preclinical inflammatory disease models. NLRP3 deubiquitination is essential for efficient NLRP3 inflammasome activity, but it remains unclear whether this process can be harnessed for therapeutic benefit. Here, we show that thiolutin (THL), an inhibitor of the JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease, blocks NLRP3 inflammasome activation by canonical, noncanonical, alternative, and transcription-independent pathways at nanomolar concentrations. In addition, THL potently inhibited the activation of multiple NLRP3 mutants linked with cryopyrin-associated periodic syndromes (CAPS). Treatment with THL alleviated NLRP3-related diseases in mouse models of lipopolysaccharide-induced sepsis, monosodium urate-induced peritonitis, experimental autoimmune encephalomyelitis, CAPS, and methionine-choline-deficient diet-induced nonalcoholic fatty liver disease. Mechanistic studies revealed that THL inhibits the BRCC3-containing isopeptidase complex (BRISC)-mediated NLRP3 deubiquitination and activation. In addition, we show that holomycin, a natural methyl derivative of THL, displays an even higher inhibitory activity against NLRP3 inflammasome than THL. Our study validates that posttranslational modification of NLRP3 can be pharmacologically targeted to prevent or treat NLRP3-associated inflammatory diseases. Future clinical development of derivatives of THL may provide new therapies for NLRP3-related diseases.

• Authors: Guang-Ming Ren, Jian Li, Xiao-Chun Zhang, Yu Wang, Yang Xiao, Xuan-Yi Zhang, Xian Liu, Wen Zhang, Wen-Bing Ma, Jie Zhang, Ya-Ting Li, Shou-Song Tao, Ting Wang, Kai Liu, Hui Chen, Yi-Qun Zhan, Miao Yu, Chang-Yan Li, Chang-Hui Ge, Bo-Xue Tian, Gui-Fang Dou, Xiao-Ming Yang, Rong-Hua Yin
• Journal: Science immunology (Sci Immunol) Vol. 6 Issue 58 (04 30 2021) ISSN: 2470-9468 [Electronic] United States
• PMID: 33931568 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• IL1B protein, mouse
• Inflammasomes
• Interleukin-18
• Interleukin-1beta
• Lactams
• Lipopolysaccharides
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Pyrrolidinones
• acetopyrrothine
• holomycin
• BRCC3 protein, mouse
• Deubiquitinating Enzymes

Topics

• Animals
• Deubiquitinating Enzymes (antagonists & inhibitors, genetics, metabolism)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, immunology)
• Female
• Fetal Blood
• Humans
• Inflammasomes (drug effects, immunology, metabolism)
• Interleukin-18 (metabolism)
• Interleukin-1beta (metabolism)
• Lactams (pharmacology, therapeutic use)
• Lipopolysaccharides
• Male
• Mice
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein (antagonists & inhibitors, genetics, metabolism)
• Non-alcoholic Fatty Liver Disease (drug therapy, immunology)
• Pregnancy
• Primary Cell Culture
• Pyrrolidinones (pharmacology, therapeutic use)
• THP-1 Cells
• Ubiquitination (drug effects)