| First Author | Maeder C | Year | 2023 |
| Journal | Front Immunol | Volume | 14 |
| Pages | 1252384 | PubMed ID | 37701434 |
| Mgi Jnum | J:340522 | Mgi Id | MGI:7527287 |
| Doi | 10.3389/fimmu.2023.1252384 | Citation | Maeder C, et al. (2023) Membrane-bound Interleukin-1alpha mediates leukocyte adhesion during atherogenesis. Front Immunol 14:1252384 |
| abstractText | INTRODUCTION: The interleukin-1 (IL-1) family and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome contribute to atherogenesis but the underlying mechanisms are incompletely understood. Unlike IL-1beta, IL-1alpha is not dependent on the NLRP3 inflammasome to exert its pro-inflammatory effects. Here, a non-genetic model was applied to characterize the role of IL-1alpha, IL-1beta, and NLRP3 for the pathogenesis of atherosclerosis. METHODS: Atherogenesis was induced by gain-of-function PCSK9-AAV8 mutant viruses and feeding of a high-fat western diet (WTD) for 12 weeks in C57Bl6/J wildtype mice (WT) and in Il1a(-/-), Nlrp3(-/-), and Il1b(-/-) mice. RESULTS: PCSK9-Il1a(-/-) mice showed reduced atherosclerotic plaque area in the aortic root with lower lipid accumulation, while no difference was observed between PCSK9-WT, PCSK9-Nlrp3(-/-) and PCSK9-Il1b(-/-) mice. Serum proteomic analysis showed a reduction of pro-inflammatory cytokines (e.g., IL-1beta, IL-6) in PCSK9-Il1a(-/-) as well as in PCSK9-Nlrp3(-/-) and PCSK9-Il1b(-/-) mice. Bone marrow dendritic cells (BMDC) of PCSK9-WT, PCSK9-Nlrp3(-/-), and PCSK9-Il1b(-/-) mice and primary human monocytes showed translocation of IL-1alpha to the plasma membrane (csIL-1alpha) upon stimulation with LPS. The translocation of IL-1alpha to the cell surface was regulated by myristoylation and increased in mice with hypercholesterolemia. CsIL-1alpha and IL1R1 protein-protein interaction on endothelial cells induced VCAM1 expression and monocyte adhesion, which was abrogated by the administration of neutralizing antibodies against IL-1alpha and IL1R1. CONCLUSION: The results highlight the importance of IL-1alpha on the cell surface of circulating leucocytes for the development of atherosclerosis. PCSK9-Il1a(-/-) mice, but not PCSK9-Nlrp3(-/-) or PCSK9-Il1b(-/-) mice, are protected from atherosclerosis after induction of hypercholesterolemia independent of circulating cytokines. Myristoylation and translocation of IL-1alpha to the cell surface in myeloid cells facilitates leukocyte adhesion and contributes to the development of atherosclerosis. |
