A Shifting Immune Landscape: ILC Redistribution and Neutrophil Polarization in Vascular Cognitive Impairment and Dementia (VCID)

Vascular cognitive impairment and dementia (VCID) is increasingly recognized as a major contributor to cognitive decline; however, the mechanisms through which vascular dysfunction drives innate immune dysregulation remain poorly understood. In this study, we explore the impact of VCID on the cerebral innate immune landscape, focusing on innate lymphoid cells (ILCs) and neutrophils, two key players in neuroinflammation and brain immune homeostasis.

Using a murine model of VCID induced by bilateral common carotid artery stenosis (BCAS) with modifications in C57BL/6 mice, we investigated innate immune cell distribution, polarization, and functional profiles using flow cytometry and immunofluorescence staining. Our findings reveal a compartment-specific shift in ILC populations, with a reduction of ILC2s in the meninges and concurrent expansion in the choroid plexus, accompanied by altered cytokine production. Furthermore, VCID drove a marked shift in neutrophil polarization toward a pro-inflammatory N1-like phenotype in both the meninges and choroid plexus. Critically, immunofluorescence staining of hippocampal brain sections confirmed that activated N1-like neutrophils, characterized by elevated IL-1β and MPO and reduced IL-10, infiltrate the hippocampal parenchyma in VCID, suggesting a spatially progressive innate immune response spanning from CNS border compartments to brain tissue.

These results identify a novel innate immune signature in VCID, compartment-specific ILC redistribution, pro-inflammatory neutrophil polarization at CNS borders, and parenchymal neutrophil infiltration in the hippocampus, which may collectively amplify neuroinflammation and accelerate cognitive decline, identifying potential therapeutic targets for vascular-related dementia.

Highlights

• VCID reduces meningeal ILC2s while driving their concurrent expansion in the choroid plexus

• N1-like neutrophil polarization is significantly enhanced in VCID meninges and choroid plexus

• Activated N1-like neutrophils infiltrate hippocampal parenchyma in VCID

• N1-like neutrophil activation in VCID is characterized by elevated MPO and IL-1β with concurrent loss of anti-inflammatory IL-10

• A spatially progressive innate immune cascade links CNS borders to brain tissue

Graphic Abstract

VCID reshapes the CNS innate immune landscape

Meningeal ILC2s are significantly reduced while choroid plexus ILC2s expand, reflecting a compartment-specific redistribution. Concurrently, pro-inflammatory N1-like neutrophils, marked by elevated MPO and IL-1β, progressively infiltrate from CNS border compartments into the hippocampal parenchyma, driving neuroinflammation and cognitive decline.