Targeting TLR4 alleviates the progression of experimental autoimmune encephalomyelitis by regulating central resident cells and Th1/Th17 cell differentiation
6 affiliations
- 1College of Life Sciences, South-Central Minzu University
- 2Wuhan Institute for Neuroscience and Neuroengineering, South-Central Minzu University
- 3State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences
- 4Department of Laboratory Medicine, The Second Affiliated Hospital of Guilin Medical University
- 5School of Undergraduate Studies, South-Central Minzu University
- 6Guangxi Key Laboratory of Metabolic Reprogramming and Intelligent Medical Engineering for Chronic Diseases, Guangxi Key Laboratory of Multimodal Biomarkers and Precision Diagnosis, Guilin Medical University
Abstract
Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by neuroinflammation. Toll-like receptor 4 (TLR4) is a receptor for damage-associated molecular patterns, such as high-mobility group box 1 (HMGB1) and plays a role in innate immunity. However, its precise role and cellular dynamics in MS pathogenesis are unclear. Using the experimental autoimmune encephalomyelitis (EAE) model, we mapped the expression dynamics of TLR4 and found that in the spinal cords, the cell type associated with the disease shifted from neurons to activated glia. To establish causality, we subjected TLR4 ⁻ / ⁻ mice to EAE and observed significantly attenuated disease severity, reduced demyelination, and preserved neuronal integrity, alongside suppressed microglial and astrocytic activation. Furthermore, TLR4 deficiency was not merely dampening CNS-localized inflammation but was also associated with suppressed peripheral MOG 35–55 -specific Th1/Th17 effector responses, as evidenced by reduced production of IFN-γ and IL-17A in lymphoid organs, together with reduced TNF-α, as well as diminished expression of the Th1/Th17 lineage-defining transcription factors T-bet and RORγt in the spinal cord infiltrates. This suggests that TLR4 plays a key role in EAE pathology by connecting peripheral Th1/Th17 differentiation with central glial inflammatory responses. Critically, to translate these findings, we evaluated the small-molecule TLR4 antagonist TAK-242. While prophylactic administration was effective, therapeutic dosing initiated after disease onset still significantly alleviated clinical scores and delayed progression, highlighting its potential for clinical intervention. Overall, our results demonstrate that targeting TLR4 simultaneously curtails pathogenic T-cell differentiation and local neuroinflammation, establishing TLR4 as a dual-action therapeutic target for MS.
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BibTeX
@article{du2026targeting,
title = {{Targeting TLR4 alleviates the progression of experimental autoimmune encephalomyelitis by regulating central resident cells and Th1/Th17 cell differentiation}},
author = {E Du and Ke Lei and Wei Deng and Siyu Yang and Yun Liu and Jiapei Dai and Jiawen Lei and Rui Zhang and Hao Tao and Huoying Chen and Yan Sun},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1973420},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973420/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting TLR4 alleviates the progression of experimental autoimmune encephalomyelitis by regulating central resident cells and Th1/Th17 cell differentiation
AU - E Du
AU - Ke Lei
AU - Wei Deng
AU - Siyu Yang
AU - Yun Liu
AU - Jiapei Dai
AU - Jiawen Lei
AU - Rui Zhang
AU - Hao Tao
AU - Huoying Chen
AU - Yan Sun
PY - 2026
DA - 2026/10/16
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1973420
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1973420/full
AB - Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by neuroinflammation. Toll-like receptor 4 (TLR4) is a receptor for damage-associated molecular patterns, such as high-mobility group box 1 (HMGB1) and plays a role in innate immunity. However, its precise role and cellular dynamics in MS pathogenesis are unclear. Using the experimental autoimmune encephalomyelitis (EAE) model, we mapped the expression dynamics of TLR4 and found that in the spinal cords, the cell type associated with the disease shifted from neurons to activated glia. To establish causality, we subjected TLR4 ⁻ / ⁻ mice to EAE and observed significantly attenuated disease severity, reduced demyelination, and preserved neuronal integrity, alongside suppressed microglial and astrocytic activation. Furthermore, TLR4 deficiency was not merely dampening CNS-localized inflammation but was also associated with suppressed peripheral MOG 35–55 -specific Th1/Th17 effector responses, as evidenced by reduced production of IFN-γ and IL-17A in lymphoid organs, together with reduced TNF-α, as well as diminished expression of the Th1/Th17 lineage-defining transcription factors T-bet and RORγt in the spinal cord infiltrates. This suggests that TLR4 plays a key role in EAE pathology by connecting peripheral Th1/Th17 differentiation with central glial inflammatory responses. Critically, to translate these findings, we evaluated the small-molecule TLR4 antagonist TAK-242. While prophylactic administration was effective, therapeutic dosing initiated after disease onset still significantly alleviated clinical scores and delayed progression, highlighting its potential for clinical intervention. Overall, our results demonstrate that targeting TLR4 simultaneously curtails pathogenic T-cell differentiation and local neuroinflammation, establishing TLR4 as a dual-action therapeutic target for MS.
SN - 1664-3224
ER -