Chronic Neuroimmune and Neurovascular Remodeling After Ischemic Stroke in Humans: From the Subacute Phase to the Chronic Infarct

Ischemic stroke initiates a prolonged sequence of neurovascular and neuroimmune remodeling processes that persist for months to years beyond the acute event and contribute to progressive neurodegeneration, white matter loss, and vascular cognitive impairment. Despite this substantial long-term burden, the biological processes characterizing the chronic post-stroke brain remain incompletely defined. In this review, we integrate human histopathological evidence with mechanistic insights from experimental stroke models to develop a conceptual framework for chronic post-stroke neuroimmune and neurovascular pathology in humans organized around six inter-related biological domains: the cerebrovasculature, the myeloid cell response, adaptive immune infiltration, glial scar formation, glymphatic function, and white matter pathology. Each domain originates as an adaptive response to ischemic injury but progressively evolves into a chronically active state that sustains, rather than resolves, the post-stroke neuroimmune environment. These domains are mechanistically coupled and collectively constitute a self-reinforcing chronic neuroimmune niche whose reparative and maladaptive dimensions coexist and shift with time, infarct context, and individual biological variation. Together, these observations support a paradigm in which the chronic infarct is not simply the residual consequence of ischemic injury but a dynamic neuroimmune microenvironment that continues to shape brain degeneration, vascular remodeling, and functional recovery months to years after stroke, making it one of the most promising therapeutic targets for promoting long-term recovery. The Chronic Infarct: A Self-Sustaining Neuroimmune Niche : Ischemic stroke triggers six interlinked processes: vascular remodeling, myeloid activation, adaptive immune infiltration, glial scarring, glymphatic dysfunction, and white matter injury, which persist for months to years, forming a self-reinforcing niche that drives chronic neurodegeneration. Created with BioRender.com.