| First Author | Yalcinkaya M | Year | 2023 |
| Journal | Cardiovasc Res | Volume | 119 |
| Issue | 4 | Pages | 969-981 |
| PubMed ID | 36537208 | Mgi Jnum | J:360032 |
| Mgi Id | MGI:7470629 | Doi | 10.1093/cvr/cvac189 |
| Citation | Yalcinkaya M, et al. (2023) Cholesterol accumulation in macrophages drives NETosis in atherosclerotic plaques via IL-1beta secretion. Cardiovasc Res 119(4):969-981 |
| abstractText | 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-1beta. METHODS AND RESULTS: We generated mice with neutrophil or macrophage-specific Abca1/g1 deficiency (S100A8CreAbca1fl/flAbcg1fl/fl or CX3CR1CreAbca1fl/flAbcg1fl/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)-1beta 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-1beta antagonism. In vitro, IL-1beta or media transferred from Abca1/g1-deficient macrophages increased NETosis in both control and Abca1/Abcg1 deficient neutrophils. This cell-extrinsic effect of IL-1beta on NETosis was blocked by an NLRP3 inhibitor. CONCLUSION: These studies establish a new link between inflammasome-mediated IL-1beta production in macrophages and NETosis in atherosclerotic plaques. Macrophage-derived IL-1beta appears to increase NETosis both by increasing neutrophil recruitment to plaques and by promoting neutrophil NLRP3 inflammasome activation. |
