Adenosine 2A receptor drives microglial efferocytosis to accelerate white matter repair and functional recovery after stroke.

Abstract

Although reperfusion therapy effectively restores blood flow to occluded brain arteries after ischemic stroke, many patients develop persistent white matter injury, a major contributor to long-term neurological disability. Currently, there are few approved clinical therapies that specifically target white matter repair to enhance functional recovery after stroke. We demonstrated that microglial adenosine 2A receptor (A2AR) is essential for spontaneous white matter regeneration after ischemic injury in mice. Deletion of A2AR in microglia specifically impaired chronic-phase repair without altering the severity of acute ischemic injury. Pharmacological activation of A2AR signaling with blood-brain barrier-permeable agonistic micelles during the early reperfusion phase enhanced white matter structural repair and led to sustained improvements in cognitive and sensorimotor function in mice. Mechanistically, A2AR activation promoted microglial efferocytosis of apoptotic cells and myelin debris in the lesioned white matter, thereby limiting secondary necrosis-induced inflammation, enhancing neurotrophic factor release, and establishing a reparative microenvironment conducive to oligodendrocyte precursor cell differentiation and remyelination. Moreover, A2AR signaling engaged HIF1α-dependent metabolic reprogramming to increase glycolysis, thereby providing the energetic support required for efficient and sustained efferocytosis. Together, these findings identify A2AR as a critical regulator of microglia-mediated white matter repair and a promising therapeutic target for enhancing regeneration after stroke.