Intravenous injection of lipid-free apolipoprotein A-I dampens inflammation by reprogramming macrophage function
High-density lipoproteins (HDLs) and their main protein, apolipoprotein A-I (apoA-I), are considered immunomodulators of the vascular wall. However, the precise mechanisms are incompletely understood. Using intravital microscopy, flow cytometry, experimental ex vivo models, and bulk RNA sequencing of cultured macrophages, this study reveals the immunomodulatory capacity of apoA-I, which is validated in representative inflammatory models. Intravital imaging in mice shows specific uptake of intravenously injected, lipid-free apoA-I by dermal perivascular macrophages. Supraphysiological doses of apoA-I alter key cellular pathways, involving mammalian target of rapamycin complex 1 (mTORC1) and interferon regulatory factor 8 (IRF8), in THP-1-derived macrophages. In lipopolysaccharide (LPS)-induced skin inflammation, apoA-I pretreatment dampens the inflammatory response and reduces immune cell trafficking in and out of the skin. Moreover, apoA-I inhibits joint inflammation in a mouse model of rheumatoid arthritis (RA). Overall, apoA-I acts as an integrator of vascular-immune interactions by modulating macrophage function in the vicinity of blood vessels. These findings open avenues for HDL-targeting strategies in a broad spectrum of autoimmune disorders, including RA.
Authors
- Lois L. Cavanagh
- Anna Kusienicka (ORCID: https://orcid.org/0000-0003-0933-2610)
- Sander W. Tas (ORCID: https://orcid.org/0000-0002-8940-1788)
- Andrew J. Mitchell (ORCID: https://orcid.org/0000-0003-4454-853X)
- Miranda Van Eck (ORCID: https://orcid.org/0000-0003-3936-3194)
- Matthias Wielscher (ORCID: https://orcid.org/0000-0003-4138-1383)
- Casper C. van Olden (ORCID: https://orcid.org/0000-0002-4594-6735)
- Rohit K. Jain (ORCID: https://orcid.org/0000-0002-9295-9360)
- Ben Roediger (ORCID: https://orcid.org/0000-0002-4593-091X)
- Peter Youssef (ORCID: https://orcid.org/0000-0002-9010-3999)
- K.-A. Rye
- Radjesh Bisoendial
- Matthias Farlik
- Wolfgang Weninger
- Georges Grau
Institutions
- Leiden University (NL)
- The University of Sydney (AU)
- Royal Prince Alfred Hospital (AU)
- Centenary Institute (AU)
- Amsterdam UMC Location University of Amsterdam (NL)
- UNSW Sydney (AU)
- Maasstad Ziekenhuis (NL)
- Centre for Human Drug Research (NL)
- Amsterdam University Medical Centers (NL)
- Medical University of Vienna (AT)
- University of Amsterdam (NL)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1016/j.celrep.2026.117212
- Primary Topic
- Cholesterol and Lipid Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- University of New South Wales
- University of Sydney
- Vienna Science and Technology Fund
- Österreichischen Akademie der Wissenschaften
- Austrian Science Fund
- ReumaNederland
- Universitätsbund Erlangen-Nürnberg
- Dutch Arthritis Association
- National Health and Medical Research Council