Single-cell profiling reveals age-associated immunity in atherosclerosis

Area of Science:

• Immunology
• Cardiovascular Science
• Gerontology

Background:

• Aging is a primary driver of atherosclerosis, leading to immunosenescence.
• Understanding aging's impact on the immune system in atherosclerosis is crucial due to a growing elderly population.
• Existing mouse models often fail to capture age-related immune changes seen in human atherosclerosis.

Purpose of the Study:

• To investigate the impact of aging on atherosclerosis development and the immune landscape in Ldlr-deficient mice.
• To identify specific age-associated immune cell populations and their functional roles in atherosclerosis.

Main Methods:

• Aged and young Ldlr-deficient mice on a chow diet were studied for atherosclerosis progression, calcification, and cholesterol crystals.
• Systemic immunosenescence markers, including myeloid skewing and T-cell phenotypes, were analyzed.
• Single-cell RNA-sequencing and flow cytometry were used on aortic leukocytes to identify age-related gene expression and cell populations.
• In vitro studies assessed the antigen-presenting capacity of identified age-associated B cells (ABCs).

Main Results:

• Aging promoted advanced atherosclerosis, characterized by increased calcification and cholesterol crystals in chow diet-fed Ldlr-/- mice.
• Systemic immunosenescence was observed, with myeloid cell skewing and T-cells exhibiting extreme effector phenotypes.
• Age-associated pro-inflammatory cells, including GzmK+CD8+ T-cells and novel CD11b+CD11c+T-bet+ ABCs, were identified in aged aortas.
• ABCs demonstrated high gene expression related to plasma cell differentiation, co-stimulation, and antigen presentation, functioning as potent antigen-presenting cells.
• These age-associated T and B cells were confirmed in atherosclerotic plaques and blood of human cardiovascular disease patients.

Conclusions:

• This study provides the first comprehensive profiling of aged immunity in an atherosclerotic mouse model.
• The emergence of specific age-associated T and B cells in the atherosclerotic aorta is a key finding.
• Further research into age-associated immunity holds potential for developing novel diagnostic and therapeutic strategies for cardiovascular disease.