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

Research paper by Ebtisam A EA Al-Ofi, Badrah S BS Al-Ghamdi

Indexed on: 15 Aug '18Published on: 15 Aug '18Published in: Folia morphologica


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.