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Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerotic Plaque Inflammation and Progression in Hyperlipidemic Mice.

ABSTRACT: T cell-driven inflammation plays a critical role in the initiation and progression of atherosclerosis. The co-inhibitory protein Cytotoxic T-Lymphocyte Associated protein (CTLA) 4 is an important negative regulator of T cell activation. Here, we studied the effects of the antibody-mediated inhibition of CTLA4 on experimental atherosclerosis by treating 6-8-week-old Ldlr-/- mice, fed a 0.15% cholesterol diet for six weeks, biweekly with 200 ?g of CTLA4 antibodies or isotype control for six weeks. 18F-fluorodeoxyglucose Positron Emission Tomography-Computed Tomography showed no effect of the CTLA4 inhibition of activity in the aorta, spleen, and bone marrow, indicating that monocyte/macrophage-driven inflammation was unaffected. Correspondingly, flow cytometry demonstrated that the antibody-mediated inhibition of CTLA4 did not affect the monocyte populations in the spleen. ?CTLA4 treatment induced an activated T cell profile, characterized by a decrease in naïve CD44-CD62L+CD4+ T cells and an increase in CD44+CD62L- CD4+ and CD8+ T cells in the blood and lymphoid organs. Furthermore, ?CTLA4 treatment induced endothelial activation, characterized by increased ICAM1 expression in the aortic endothelium. In the aortic arch, which mainly contained early atherosclerotic lesions at this time point, ?CTLA4 treatment induced a 2.0-fold increase in the plaque area. These plaques had a more advanced morphological phenotype and an increased T cell/macrophage ratio, whereas the smooth muscle cell and collagen content decreased. In the aortic root, a site that contained more advanced plaques, ?CTLA4 treatment increased the plaque T cell content. The short-term antibody-mediated inhibition of CTLA4 thus accelerated the progression of atherosclerosis by inducing a predominantly T cell-driven inflammation, and resulted in the formation of plaques with larger necrotic cores and less collagen. This indicates that existing therapies that are based on ?CTLA4 antibodies may promote CVD development in patients.

SUBMITTER: Poels K

PROVIDER: S-EPMC7565685 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerotic Plaque Inflammation and Progression in Hyperlipidemic Mice.

Poels Kikkie K van Leent Mandy M T MMT Reiche Myrthe E ME Kusters Pascal J H PJH Huveneers Stephan S de Winther Menno P J MPJ Mulder Willem J M WJM Lutgens Esther E Seijkens Tom T P TTP

Cells 20200829 9

T cell-driven inflammation plays a critical role in the initiation and progression of atherosclerosis. The co-inhibitory protein Cytotoxic T-Lymphocyte Associated protein (CTLA) 4 is an important negative regulator of T cell activation. Here, we studied the effects of the antibody-mediated inhibition of CTLA4 on experimental atherosclerosis by treating 6-8-week-old Ldlr<sup>-/-</sup> mice, fed a 0.15% cholesterol diet for six weeks, biweekly with 200 μg of CTLA4 antibodies or isotype control for ...[more]

PMID: 32872393

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Project description:BackgroundAtherosclerosis progression during aging culminates in the development of vulnerable plaques, which may increase the risk of cardiovascular events. Increased generation and/or decreased scavenging of reactive oxygen species in the vascular wall are major contributors to atherogenesis. We previously showed that superoxide dismutase 2 deficiency increased vascular oxidative stress and reduced aortic compliance in aged wild-type mice and that young Apoe-/-/Sod2+/- had increased mitochondrial DNA damage and atherosclerosis versus young Apoe-/- mice. Here we investigated the effects of superoxide dismutase 2 deficiency on atherosclerosis progression and plaque morphology in middle-aged Apoe-/- mice.Methods and resultsCompared with Apoe-/-, middle-aged Apoe-/-/Sod2+/- mice had increased vascular wall reactive oxygen species (P<0.05) and higher atherosclerotic lesion area (P<0.001). The atherosclerotic plaques in middle-aged Apoe-/-/Sod2+/- mice had an increased necrotic core with higher inflammatory cell infiltration, a thinned fibrous cap with depleted smooth muscle content, and intraplaque hemorrhage. In addition, the plaque shoulder area had higher levels of calpain-2, caspase-3, and matrix metalloproteinase-2 in intimal smooth muscle cells and depleted fibrous cap collagen. Targeting mitochondrial reactive oxygen species with MitoTEMPO attenuated features of atherosclerotic plaque vulnerability in middle-aged Apoe-/-/Sod2+/- mice by lowering expression of calpain-2, caspase-3, and matrix metalloproteinase-2 and decreasing smooth muscle cell apoptosis and matrix degradation.ConclusionsEnhanced mitochondrial oxidative stress under hyperlipidemic conditions in aging induces plaque instability, in part by increasing smooth muscle cell apoptosis, necrotic core expansion, and matrix degradation. Targeting mitochondrial reactive oxygen species or its effectors may be a viable therapeutic strategy to prevent aging-associated and oxidative stress-related atherosclerosis complications.

Dataset Information

Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerotic Plaque Inflammation and Progression in Hyperlipidemic Mice.

Publications

Antibody-Mediated Inhibition of CTLA4 Aggravates Atherosclerotic Plaque Inflammation and Progression in Hyperlipidemic Mice.

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