Specific NLRP3 Inhibition Protects Against Diabetes-Associated Atherosclerosis

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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)772-787
Number of pages16
JournalDiabetes
Volume70
Issue number3
DOIs
Publication statusPublished - Mar 2021

Keywords

  • NLRP3 inflammasome
  • ATHEROSCLEROSIS
  • Inflammation
  • IL-1 β
  • Oxidative stress

Cite this