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.