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Peer-reviewedCC BY 4.0Frontiers in Immunology

Immune-endothelial crosstalk at the nexus of neuroinflammation and vascular dysfunction in aging

  • Zhitao Cui1
  • Huaiyu Sun2
  • Zhiqing Chen2,3,4
  • Jiaai Li2
4 affiliations
  1. 1Department of Geriatrics, The First Hospital of Jilin University
  2. 2Department of Neurology, The First Hospital of Jilin University
  3. 3Department of Neurology, Beijing Tiantan Hospital, Capital Medical University
  4. 4Human Brain and Tissue Bank, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University
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Abstract

Aging is the major biological risk factor for cognitive decline and neurodegenerative disease. Increasing evidence indicates that neuroinflammation and cerebrovascular dysfunction are not independent consequences of aging but interact through the neurovascular interface. Cerebrovascular endothelial cells are central to this interaction because they form the blood–brain barrier (BBB) while actively regulating vascular tone, molecular transport, leukocyte trafficking, and inflammatory signaling. Here, we review how aging simultaneously primes immune and endothelial compartments through microglial sensitization, astrocytic remodeling, systemic inflammaging, endothelial senescence, altered transcytosis, oxidative stress, and senescence-associated inflammatory signaling. Immune-derived cytokines, reactive oxygen species, matrix metalloproteinases, complement signals, and inflammasome-related pathways can impair endothelial homeostasis, whereas aged endothelial cells relay systemic inflammatory signals through adhesion molecules, chemokines, complement receptors, and altered barrier transport. These reciprocal interactions can destabilize BBB function, cerebral blood flow regulation, and the broader neurovascular unit. Importantly, physiological aging should not be equated with neurodegenerative disease; rather, it may establish a compensated but vulnerable immune–endothelial state that is amplified by disease-specific modifiers. We discuss competing immune-first, vascular-first, and parallel-aging models and evaluate emerging therapeutic strategies aimed at restoring neurovascular homeostasis.

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Cite

BibTeXRIS
BibTeX
@article{cui2026immuneendothelial,
  title = {{Immune-endothelial crosstalk at the nexus of neuroinflammation and vascular dysfunction in aging}},
  author = {Zhitao Cui and Huaiyu Sun and Zhiqing Chen and Jiaai Li},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1972284},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1972284/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Immune-endothelial crosstalk at the nexus of neuroinflammation and vascular dysfunction in aging
AU  - Zhitao Cui
AU  - Huaiyu Sun
AU  - Zhiqing Chen
AU  - Jiaai Li
PY  - 2026
DA  - 2026/10/19
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1972284
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1972284/full
AB  - Aging is the major biological risk factor for cognitive decline and neurodegenerative disease. Increasing evidence indicates that neuroinflammation and cerebrovascular dysfunction are not independent consequences of aging but interact through the neurovascular interface. Cerebrovascular endothelial cells are central to this interaction because they form the blood–brain barrier (BBB) while actively regulating vascular tone, molecular transport, leukocyte trafficking, and inflammatory signaling. Here, we review how aging simultaneously primes immune and endothelial compartments through microglial sensitization, astrocytic remodeling, systemic inflammaging, endothelial senescence, altered transcytosis, oxidative stress, and senescence-associated inflammatory signaling. Immune-derived cytokines, reactive oxygen species, matrix metalloproteinases, complement signals, and inflammasome-related pathways can impair endothelial homeostasis, whereas aged endothelial cells relay systemic inflammatory signals through adhesion molecules, chemokines, complement receptors, and altered barrier transport. These reciprocal interactions can destabilize BBB function, cerebral blood flow regulation, and the broader neurovascular unit. Importantly, physiological aging should not be equated with neurodegenerative disease; rather, it may establish a compensated but vulnerable immune–endothelial state that is amplified by disease-specific modifiers. We discuss competing immune-first, vascular-first, and parallel-aging models and evaluate emerging therapeutic strategies aimed at restoring neurovascular homeostasis.
SN  - 1664-3224
ER  -