Klaus Ley

La Jolla, USA

Klaus Ley is Professor and Head of the Division of Inflammation Biology at the La Jolla Institute for Allergy and Immunology and Adjunct Professor of Bioengineering at the University of California, San Diego, USA. He trained at Julius-Maximilians-Universität in Würzburg, Germany and was a Professor of Bioengineering at the University of Virginia from 1994 to 2007. His research focuses on chronic inflammatory diseases such as atherosclerosis, specifically the role of myeloid leukocytes. Professor Ley is the recipient of AHA Distinguished Scientist [2015], the 2010 Malpighi Award from the European Society for Microcirculation, and the 2008 Bonazinga Award from the Society for Leukocyte Biology.

 


Monday 27 May 09:00

Macrophage immunometabolism: opportunities for phenotypical modulation?

Atherosclerosis is a chronic inflammatory disease that is driven by subendothelial accumulation of low-density lipoprotein in the arterial wall. The retained lipoproteins provoke a series of maladaptive immune responses that in turn promote plaque progression and eventually rupture. Monocytes are important mediators of the inflammatory responses involved in atherosclerosis progression. Their differentiation to macrophages, and phenotypic characterization of these macrophages, can be modulated by microenvironmental signals within the artery wall, including oxidized lipids, Toll-like receptor ligands, hematopoietic growth factors, cytokines, and chemokines. Dynamic modulation of macrophage phenotypes affects atherosclerosis progression by modulating the inflammatory responses within the vessel wall. On this basis, therefore, macrophage phenotype modulation represents an attractive therapeutic target.

Atherosclerotic plaques contain T cells, most of which are CD4+ T cells in humans. A key step in the immune response is the activation of T cells by antigens. Peptide epitopes from apolipoprotein B (apoB) have been shown to act as atherosclerosis-related autoantigens, by binding to major histocompatibility complex class II molecules and inducing specific T cell responses. Recently, apoB peptide18 was identified as the first regulatory T cell epitope in human atherosclerosis. In animal models, vaccination with p18 prevented atherosclerosis. Other studies have focused on the role of myeloid epsins, a family of ubiquitin-binding endocytic adaptors, in the regulation of atherogenicity. These epsins appear to promote atherogenesis by facilitating proinflammatory macrophage recruitment and inhibiting efferocytosis. Therefore, manipulating the adaptive immune system by vaccination or immunomodulatory strategies may offer future therapeutic potential in preventing and treating atherosclerosis.

Key references

Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res 2019;124:315-27.

Ley K, Hoffman HM, Kubes P, Cassatella MA, Zychlinsky A, Hedrick CC, Catz SD. Neutrophils: New insights and open questions. Sci Immunol 2018;3(30). pii: eaat4579.

Kimura T, Kobiyama K, Winkels H, Tse K, Miller J, Vassallo M, Wolf D, Ryden C, Orecchioni M, Dileepan T, Jenkins MK, James EA, Kwok WW, Hanna DB, Kaplan RC, Strickler HD, Durkin HG, Kassaye SG, Karim R, Tien PC, Landay AL, Gange SJ, Sidney J, Sette A, Ley K. Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B. Circulation 2018;138:1130-43.