Interleukin-23 receptor expressing γδT cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice

Gil-Pulido J, Amezaga N, Jorgacevic I, Manthey HD, Roesch M, Brand T, Cidlinsky P, Schafer S, Beilhack A, Saliba AE, Lorenz K, Boon L, Prinz I, Waisman A, Korn T, Cochain C, Zernecke A (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Cardiovascular Research Oxford University Press

Book Volume: 118

Pages Range: 2932-2945

Journal Issue: 14

DOI: 10.1093/cvr/cvab359

Abstract

Aims: Atherosclerosis is a chronic inflammatory disease of the vessel wall controlled by local and systemic immune responses. The role of interleukin-23 receptor (IL-23R), expressed in adaptive immune cells (mainly T-helper 17 cells) and γδT cells, in atherosclerosis is only incompletely understood. Here, we investigated the vascular cell types expressing IL-23R and addressed the function of IL-23R and γδT cells in atherosclerosis. Methods and results: IL-23R+ cells were frequently found in the aortic root in contrast to the aorta in low-density lipoprotein receptor deficient IL-23R reporter mice (Ldlr-/-Il23rgfp/+), and mostly identified as γδT cells that express IL-17 and GM-CSF. scRNA-seq confirmed γδT cells as the main cell type expressing Il23r and Il17a in the aorta. Ldlr-/-Il23rgfp/gfp mice deficient in IL-23R showed a loss of IL-23R+ cells in the vasculature, and had reduced atherosclerotic lesion formation in the aortic root compared to Ldlr-/- controls after 6 weeks of high-fat diet feeding. In contrast, Ldlr-/-Tcrδ-/- mice lacking all γδT cells displayed unaltered early atherosclerotic lesion formation compared to Ldlr-/- mice. In both HFD-fed Ldlr-/-Il23rgfp/gfp and Ldlr-/-Tcrδ-/- mice a reduction in the plaque necrotic core area was noted as well as an expansion of splenic regulatory T cells. In vitro, exposure of bone marrow-derived macrophages to both IL-17A and GM-CSF induced cell necrosis, and necroptotic RIP3K and MLKL expression, as well as inflammatory mediators. Conclusions: IL-23R+ γδT cells are predominantly found in the aortic root rather than the aorta and promote early atherosclerotic lesion formation, plaque necrosis, and inflammation at this site. Targeting IL-23R may thus be explored as a therapeutic approach to mitigate atherosclerotic lesion development.

Involved external institutions

Universitätsklinikum Würzburg DE Germany (DE) JJP Biologics PL Poland (PL) Julius-Maximilians-Universität Würzburg DE Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Helmholtz-Zentrum für Infektionsforschung (HZI) DE Germany (DE) Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE)

How to cite

APA:

Gil-Pulido, J., Amezaga, N., Jorgacevic, I., Manthey, H.D., Roesch, M., Brand, T.,... Zernecke, A. (2022). Interleukin-23 receptor expressing γδT cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice. Cardiovascular Research, 118(14), 2932-2945. https://dx.doi.org/10.1093/cvr/cvab359

MLA:

Gil-Pulido, Jesus, et al. "Interleukin-23 receptor expressing γδT cells locally promote early atherosclerotic lesion formation and plaque necrosis in mice." Cardiovascular Research 118.14 (2022): 2932-2945.

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