Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis.

Abstract

Low-grade persistent inflammation is a feature of diabetes-driven vascular complications, in particular activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to trigger the maturation and release of the inflammatory cytokine interleukin-1β (IL-1β). We investigated whether inhibiting the NLRP3 inflammasome, through the use of the specific small-molecule NLRP3 inhibitor MCC950, could reduce inflammation, improve vascular function, and protect against diabetes-associated atherosclerosis in the streptozotocin-induced diabetic apolipoprotein E-knockout mouse. Diabetes led to an approximately fourfold increase in atherosclerotic lesions throughout the aorta, which were significantly attenuated with MCC950 (P < 0.001). This reduction in lesions was associated with decreased monocyte-macrophage content, reduced necrotic core, attenuated inflammatory gene expression (IL-1β, tumor necrosis factor-α, intracellular adhesion molecule 1, and MCP-1; P < 0.05), and reduced oxidative stress, while maintaining fibrous cap thickness. Additionally, vascular function was improved in diabetic vessels of mice treated with MCC950 (P < 0.05). In a range of cell lines (murine bone marrow-derived macrophages, human monocytic THP-1 cells, phorbol 12-myristate 13-acetate-differentiated human macrophages, and aortic smooth muscle cells from humans with diabetes), MCC950 significantly reduced IL-1β and/or caspase-1 secretion and attenuated leukocyte-smooth muscle cell interactions under high glucose or lipopolysaccharide conditions. In summary, MCC950 reduces plaque development, promotes plaque stability, and improves vascular function, suggesting that targeting NLRP3-mediated inflammation is a novel therapeutic strategy to improve diabetes-associated vascular disease.

• Authors: Arpeeta Sharma, Judy S Y Choi, Nada Stefanovic, Annas Al-Sharea, Daniel S Simpson, Nigora Mukhamedova, Karin Jandeleit-Dahm, Andrew J Murphy, Dmitri Sviridov, James E Vince, Rebecca H Ritchie, Judy B de Haan
• Journal: Diabetes (Diabetes) Vol. 70 Issue 3 Pg. 772-787 (03 2021) ISSN: 1939-327X [Electronic] United States
• PMID: 33323396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by the American Diabetes Association.

Chemical References

• Apolipoproteins E
• Blood Glucose
• Inflammasomes
• Lipopolysaccharides
• NLR Family, Pyrin Domain-Containing 3 Protein
• Tumor Necrosis Factor-alpha
• 4-O-methyl-12-O-tetradecanoylphorbol 13-acetate
• Glucose
• Tetradecanoylphorbol Acetate

Topics

• Animals
• Apolipoproteins E (genetics, metabolism)
• Atherosclerosis (genetics, metabolism)
• Blood Glucose (metabolism)
• Cells, Cultured
• Fluorescent Antibody Technique
• Glucose (pharmacology)
• Humans
• Immunohistochemistry
• Inflammasomes (genetics, metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myocytes, Smooth Muscle (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Oxidative Stress (drug effects, genetics)
• THP-1 Cells
• Tetradecanoylphorbol Acetate (analogs & derivatives, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)