Aging alters the immunological response to ischemic stroke

Area of Science:

• Immunology
• Neuroscience
• Gerontology

Background:

• Aging significantly impacts the peripheral immune system's response to brain injury, like ischemic stroke.
• Inflammatory responses post-stroke are often heightened in older individuals, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate age-related alterations in leukocyte composition and function following ischemic stroke.
• To determine the role of peripheral immune senescence in stroke-induced inflammation and outcomes.
• To explore the potential of bone marrow manipulation for mitigating age-related stroke pathology.

Main Methods:

• Comparative analysis of circulating and infiltrating leukocytes in young versus old male mice post-stroke.
• Assessment of neutrophil phagocytic potential, reactive oxygen species production, and matrix metalloproteinase-9 (MMP-9) activity.
• Utilized heterochronic bone marrow chimeras to study the impact of immune cell age on stroke response.
• Evaluated behavioral recovery, brain pathology, and hemorrhagic transformation in chimeric mice.

Main Results:

• Aged mice exhibited increased blood neutrophilia and neutrophil infiltration into the brain post-stroke.
• Infiltrating neutrophils in aged mice showed reduced phagocytosis and elevated MMP-9 and reactive oxygen species production.
• Hemorrhagic transformation was more severe in aged mice and correlated with MMP-9 expression and neutrophil presence.
• Reconstitution of aged mice with young bone marrow improved behavioral outcomes and reduced brain neutrophil infiltration.
• Young mice receiving aged bone marrow showed increased hemorrhagic transformation.

Conclusions:

• Age-dependent changes in peripheral myeloid cell function, particularly neutrophils, worsen stroke outcomes.
• Peripheral immune senescence originating from bone marrow contributes significantly to age-related stroke pathology.
• Reversing peripheral immune senescence through bone marrow manipulation offers a potential therapeutic strategy for stroke in the elderly.