Membrane-bound Interleukin-1α mediates leukocyte adhesion during atherogenesis

• Verfasst von: Mäder, Christina [VerfasserIn]
• Verfasst von: Speer, Timotheus [VerfasserIn]
• Verfasst von: Wirth, Angela [VerfasserIn]
• Verfasst von: Boeckel, Jes-Niels [VerfasserIn]
• Verfasst von: Fatima, Sameen [VerfasserIn]
• Verfasst von: Shahzad Hussain, Khurrum [VerfasserIn]
• Verfasst von: Freichel, Marc [VerfasserIn]
• Verfasst von: Laufs, Ulrich [VerfasserIn]
• Verfasst von: Gaul, Susanne [VerfasserIn]
• Titel: Membrane-bound Interleukin-1α mediates leukocyte adhesion during atherogenesis
• Verf.angabe: Christina Maeder, Thimoteus Speer, Angela Wirth, Jes-Niels Boeckel, Sameen Fatima, Khurrum Shahzad, Marc Freichel, Ulrich Laufs and Susanne Gaul
• E-Jahr: 2023
• Jahr: 28 August 2023
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 26.01.2026
• Titel Quelle: Enthalten in: Frontiers in immunology
• Ort Quelle: Lausanne : Frontiers Media, 2010
• Jahr Quelle: 2023
• Band/Heft Quelle: 14(2023)
• ISSN Quelle: 1664-3224
• DOI: doi:10.3389/fimmu.2023.1252384
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1879113597

Abstract

IntroductionThe 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-1β, IL-1α 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-1α, IL-1β, and NLRP3 for the pathogenesis of atherosclerosis.MethodsAtherogenesis 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.ResultsPCSK9-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-1β, 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-1α to the plasma membrane (csIL-1α) upon stimulation with LPS. The translocation of IL-1α to the cell surface was regulated by myristoylation and increased in mice with hypercholesterolemia. CsIL-1α 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-1α and IL1R1.ConclusionThe results highlight the importance of IL-1α 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-1α to the cell surface in myeloid cells facilitates leukocyte adhesion and contributes to the development of atherosclerosis.