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Folia Morphol (Warsz). 2018 Aug 14. doi: 10.5603/FM.a2018.0068. [Epub ahead of print]

High-Mobility Group Box 1 (HMGB1), an Endogenous Ligand of Toll-Like Receptors 2 and 4, Induces Astroglial Inflammation via NF-ҡβ Pathway.

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Department of Physiology and Neuroscience Research Unit, King Abdulaziz University, Faculty of Medicine, Jeddah 21589, Saudi Arabia.


Neuroinflammation has a definitive role in neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. In addition to its pathogenic ligands, toll-like receptors (TLRs) can be activated by damaged endogenous molecules that induce inflammatory signalling pathways such as high-mobility group box 1 protein (HMGB1). Using an ex-vivo rat optic nerve (RON) model, we sought to determine the effects of lipopolysaccharides (LPS; TLR4 agonist), zymosan (TLR2 agonist) or HMGB1-with or without TLR2/4 antagonists, on the expression of glial fibrillary acidic protein (GFAP) and nuclear factor kappa B (NF-ҡβ) for signalling pathway and astrocyte reactivity, using double immunohistochemistry; as well as on the modulation of the neurotoxicity. HMGB1-treated RON had significant higher expression and co-localisation of GFAP and NF‑ҡβ as compared to the untreated control, which was a similar result to those treated with LPS and zymosan. Moreover, the HMGB1-induced inflammation was blocked by TLR2/4 antagonists (P=0.05). However, the HMGB1-induced cell death was unblocked by TLR antagonists. Overall, HMGB1 endogenously mediates the signalling mechanisms of neuroinflammation through TLR2/4. Whereas, the neuronal death mechanism resulting from HMGB1 could be caused by a different signalling pathway. Gaining an understanding of these mechanisms may help researchers discover new therapeutic targets for neurodegenerative diseases.


HMGB1; Immunohistochemistry; Signalling pathway; toll-like receptors

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