Peripheral RIPK2 degradation improves neurological outcomes after experimental ischemic stroke

Area of Science:

• Neuroscience
• Immunology
• Pharmacology

Background:

• Receptor-interacting serine/threonine kinase 2 (RIPK2) plays a key role in inflammatory responses.
• Ischemic stroke triggers significant inflammatory processes, contributing to secondary brain injury.
• Targeting RIPK2 presents a potential therapeutic strategy for managing post-stroke inflammation.

Purpose of the Study:

• To investigate the efficacy of a novel proteolysis targeting chimera (PROTAC) for degrading RIPK2 in vivo.
• To evaluate the therapeutic potential of RIPK2 degradation in a rodent model of ischemic stroke.
• To explore the role of peripheral RIPK2 degradation in stroke outcomes.

Main Methods:

• Developed and characterized a RIPK2-specific PROTAC.
• Established dose-response and time-course studies of RIPK2 degradation in naïve mice.
• Utilized the transient middle cerebral artery occlusion (tMCAO) model to induce ischemic stroke in rodents.
• Assessed RIPK2 degradation in brain and peripheral organs, infarct volume, and behavioral outcomes.

Main Results:

• The RIPK2 PROTAC effectively degraded RIPK2 in peripheral organs but not in the brain.
• No significant reduction in infarct volume was observed.
• Significant improvements in behavioral outcomes, including open field test, weight grip test, and neurological deficit scoring, were noted.
• Spleen involvement in the peripheral immune response post-stroke was highlighted.

Conclusions:

• RIPK2 is an important mediator of the post-stroke inflammatory response.
• Peripheral RIPK2 degradation via PROTAC shows therapeutic promise for improving functional recovery after ischemic stroke.
• The spleen plays a critical role in the secondary injury cascade following ischemic stroke, suggesting peripheral immune modulation as a therapeutic target.