LDL-Binding IL-10 Reduces Vascular Inflammation in Atherosclerotic Mice.

Autor: Volpatti LR; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States.; Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, United States.; Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL 60208, United States., de Matos SN; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States.; Medical Scientist Training Program, Pritzker School of Medicine, University of Chicago, IL, 60637, United States., Borjas G; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States., Reda J; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States., Watkins EA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States., Zhou Z; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States.; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637, United States., Nguyen M; Animal Resources Center, University of Chicago, Chicago, IL 60637, United States., Solanki A; Animal Resources Center, University of Chicago, Chicago, IL 60637, United States., Fang Y; Biological Sciences Division, Department of Medicine, University of Chicago, Chicago, IL 60637, United States.; Committee on Molecular Metabolism and Nutrition, Biological Sciences Division, University of Chicago, Chicago, IL, USA.; Committee on Molecular Medicine, University of Chicago, Chicago, IL, 60637, United States., Hubbell JA; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL 60637, United States.; Committee on Immunology, University of Chicago, Chicago, IL 60637, United States.; Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, United States.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 06. Date of Electronic Publication: 2024 Mar 06.
DOI: 10.1101/2024.03.04.582839
Abstrakt: Atherosclerosis is a chronic inflammatory disease associated with the accumulation of low-density lipoprotein (LDL) in arterial walls. Higher levels of the anti-inflammatory cytokine IL-10 in serum are correlated with reduced plaque burden. However, cytokine therapies have not translated well to the clinic, partially due to their rapid clearance and pleiotropic nature. Here, we engineered IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we constructed fusion proteins in which one domain is IL-10 and the other is an antibody fragment (Fab) that binds to protein epitopes of LDL. In murine models of atherosclerosis, we show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques. One such construct, 2D03-IL-10, significantly reduces aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that 2D03-IL-10 preferentially associates with foamy macrophages and reduces pro-inflammatory activation markers. This platform technology can be applied to a variety of therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.
Databáze: MEDLINE