Cholesterol accumulation in macrophages drives NETosis in atherosclerotic plaques via IL-1β secretion. Issue 4 (20th December 2022)

• Record Type: Journal Article
• Authors: Yalcinkaya, Mustafa; Fotakis, Panagiotis; Liu, Wenli; Endo-Umeda, Kaori; Dou, Huijuan; Abramowicz, Sandra; Xiao, Tong; Libby, Peter; Wang, Nan; Tall, Alan R; Westerterp, Marit
• Is Part Of: Cardiovascular research. Volume 119:Issue 4(2023)
• Page Start: 969
• Page End: 981
• Publication Date: 2022-12-20
• Subjects: Atherosclerosis -- Leukocyte -- Inflammation; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac189
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Neutrophil extracellular trap formation (NETosis) increases atherosclerotic plaque vulnerability and athero-thrombosis. However, mechanisms promoting NETosis during atherogenesis are poorly understood. We have shown that cholesterol accumulation due to myeloid cell deficiency of the cholesterol transporters ATP Binding Cassette A1 and G1 (ABCA1/G1) promotes NLRP3 inflammasome activation in macrophages and neutrophils and induces prominent NETosis in atherosclerotic plaques. We investigated whether NETosis is a cell-intrinsic effect in neutrophils or is mediated indirectly by cellular crosstalk from macrophages to neutrophils involving IL-1β. Methods and results: We generated mice with neutrophil or macrophage-specific Abca1/g1 deficiency ( S100A8CreAbca1 fl/fl Abcg1 fl/fl or CX3CR1CreAbca1 fl/fl Abcg1 fl/fl mice, respectively), and transplanted their bone marrow into low-density lipoprotein receptor knockout mice. We then fed the mice a cholesterol-rich diet. Macrophage, but not neutrophil Abca1/g1 deficiency activated inflammasomes in macrophages and neutrophils, reflected by caspase-1 cleavage, and induced NETosis in plaques. NETosis was suppressed by administering an interleukin (IL)-1β neutralizing antibody. The extent of NETosis in plaques correlated strongly with the degree of neutrophil accumulation, irrespective of blood neutrophil counts, and neutrophil accumulation was decreased by IL-1β antagonism. In vitro, IL-1β or media transferred from Abca1/g1 -deficient macrophages increased NETosis in both control and Abca1/Abcg1 deficient neutrophils. This cell-extrinsic effect of IL-1β on NETosis was blocked by an NLRP3 inhibitor. Conclusion: These studies establish a new link between inflammasome-mediated IL-1β production in macrophages and NETosis in atherosclerotic plaques. Macrophage-derived IL-1β appears to increase NETosis both by increasing neutrophil recruitment to plaques and by promoting neutrophil NLRP3 inflammasome activation. Graphical Abstract: Graphical abstract