EXPRESS: Toll Like Receptor 4 (TLR4) in Neuroinflammation: From Acute Hemorrhagic Stroke to Chronic Neurodegeneration.

Authors

Hadi Hasan Choudhary, Jun Yoshida, Rezwanul Islam, Zhaoyuan Wang, Khalid A Hanafy

Published in

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. Pages 271678X261468877. Jul 03, 2026. Epub Jul 03, 2026.

Abstract

Subarachnoid Hemorrhage (SAH) remains a leading cause of morbidity and mortality worldwide. While the primary injury is defined by mechanical tissue disruption, the progression of secondary brain injury is largely driven by robust neuroinflammatory cascades initiated by blood derived damage-associated molecular patterns (DAMPs). Among the key mediators of this response, Toll-like receptor 4 (TLR4) has emerged as a central regulator. TLR4 activation in microglia triggers downstream signaling through both MyD88 dependent and TRIF dependent pathways, driving the production of pro inflammatory cytokines and type I interferons. Additionally, non-canonical regulation of TLR4 by Lyn kinase introduces a critical modulatory mechanism that can shift microglial responses between inflammatory and phagocytic phenotypes in a sex dependent manner. Beyond hemorrhagic stroke, TLR4 mediated neuroinflammation also plays a significant role in the progression of Alzheimer's disease, where it influences amyloid-β recognition, clearance, and chronic glial activation. Emerging therapeutic strategies targeting TLR4 and its downstream signaling components including small molecules, natural compounds, aptamers, and TLR4-Lyn interaction modulators demonstrate promising potential in attenuating neuroinflammation and improving neurological outcomes. This review highlights the molecular mechanisms of TLR4 signaling in neuroinflammation and underscores its translational relevance as a therapeutic target in both acute and chronic neurodegenerative conditions.

PMID:
42400119
Bibliographic data and abstract were imported from PubMed on 04 Jul 2026.

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