T lymphocyte-derived extracellular vesicles aggravate abdominal aortic aneurysm by promoting macrophage lipid peroxidation and migration via pyruvate kinase muscle isozyme 2

• Published in: Redox biology Vol. 50; p. 102257
• Main Authors: Dang, Guohui, Li, Tianrun, Yang, Dongmin, Yang, Guangxin, Du, Xing, Yang, Juan, Miao, Yutong, Han, Lulu, Ma, Xiaolong, Song, Yuwei, Liu, Bo, Li, Xuan, Wang, Xian, Feng, Juan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2022; Elsevier
• Subjects: Abdominal aortic aneurysm; Animals; Aortic Aneurysm, Abdominal - chemically induced; Aortic Aneurysm, Abdominal - metabolism; Carrier Proteins; Disease Models, Animal; Extracellular Vesicles; Humans; Lipid Peroxidation; Macrophage migration; Macrophages - metabolism; Membrane Proteins; Mice; Mice, Inbred C57BL; Pyruvate Kinase - metabolism; Pyruvate kinase muscle isozyme 2; Research Paper; T-Lymphocytes - metabolism; Thyroid Hormone-Binding Proteins; Thyroid Hormones; Extracellular vesicles; Macrophage migration; Lipid peroxidation; Pyruvate kinase muscle isozyme 2; Abdominal aortic aneurysm
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2022.102257

T lymphocyte and macrophage infiltration in the aortic wall is critical for abdominal aortic aneurysm (AAA). However, how T lymphocytes interact with macrophages in the pathogenesis of AAA remains largely uncharacterized. In an elastase-induced murine AAA model, we first found that the expression of pyruvate kinase muscle isozyme 2 (PKM2), the last rate-limiting enzyme in glycolysis, was increased in infiltrated T lymphocytes of vascular lesions. T lymphocyte-specific PKM2 deficiency in mice (LckCrePKM2fl/fl) or intraperitoneal administration of the sphingomyelinase inhibitor GW4869 caused a significant attenuation of the elastase-increased aortic diameter, AAA incidence, elastic fiber disruption, matrix metalloproteinases (MMPs) expression, and macrophage infiltration in the vascular adventitia compared with those in PKM2fl/fl mice. Mechanistically, extracellular vesicles (EVs) derived from PKM2-activated T lymphocytes elevated macrophage iron accumulation, lipid peroxidation, and migration in vitro, while macrophages treated with EVs from PKM2-null T lymphocytes or pretreated with the lipid peroxidation inhibitors ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1), or the iron chelating agent deferoxamine mesylate (DFOM) reversed these effects. In vascular lesions of elastase-induced LckCrePKM2fl/fl mice with AAA, the oxidant system weakened, with downregulated 4-hydroxynonenal (4-HNE) levels and strengthened antioxidant defense systems with upregulated glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter solute carrier family 7 member 11 (Slc7a11) expressions in macrophages. High-throughput metabolomics showed that EVs derived from PKM2-activated T lymphocytes contained increased levels of polyunsaturated fatty acid (PUFA)-containing phospholipids, which may provide abundant substrates for lipid peroxidation in target macrophages. More importantly, upregulated T lymphocyte PKM2 expression was also found in clinical AAA subjects, and EVs isolated from AAA patient plasma enhanced macrophage iron accumulation, lipid peroxidation, and migration ex vivo. Therefore, from cell-cell crosstalk and metabolic perspectives, the present study shows that PKM2-activated T lymphocyte-derived EVs may drive AAA progression by promoting macrophage redox imbalance and migration, and targeting the T lymphocyte-EV-macrophage axis may be a potential strategy for early warning and treating AAA. [Display omitted]