Dataset Information

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

ABSTRACT:

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-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.

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-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.

Conclusion

The 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.

SUBMITTER: Maeder C

PROVIDER: S-EPMC10494239 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

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

Maeder Christina C Speer Thimoteus T Wirth Angela A Boeckel Jes-Niels JN Fatima Sameen S Shahzad Khurrum K Freichel Marc M Laufs Ulrich U Gaul Susanne S

Frontiers in immunology 20230828

<h4>Introduction</h4>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-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.<h4>Methods</h4>Atherogenesis was induced by gain-of-function ...[more]

PMID: 37701434

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Dataset Information

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

Introduction

Methods

Results

Conclusion

Publications

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

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