Targeting the transcription factor SPI1 attenuates neuroinflammation and dopaminergic degeneration in Parkinson’s disease via the tim-3/NF-κb axis
- 1Department of Neurology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China
Abstract
Microglia-mediated neuroinflammation is a critical driver of dopaminergic neuronal loss in Parkinson’s disease (PD), presenting a viable target for disease-modifying therapies. Although the transcription factor Spi-1 proto-oncogene (SPI1) is implicated in microglial regulation, its specific pathological role and therapeutic potential in PD remain elusive. In this study, utilizing in vivo MPTP-induced mouse models and in vitro MPP + stimulated microglia, we identified SPI1 as a crucial regulator of PD-associated neuroinflammation. We found that SPI1 expression is aberrantly upregulated in both PD models. Crucially, SPI1 knockdown significantly mitigated motor deficits, attenuated dopaminergic neuronal loss, and suppressed neuroinflammation by reducing proinflammatory cytokines. Mechanistically, we revealed that SPI1 directly binds to the promoter of T-cell immunoglobulin and mucin-domain-containing 3 (TIM-3) to activate its transcription. Silencing SPI1 facilitated a neuroprotective microglial M1-to-M2 phenotypic shift by downregulating TIM-3 and subsequently inhibiting the NF-κB signaling pathway, thereby protecting against synaptic impairment and neuronal apoptosis. Together, our findings elucidate a novel SPI1/TIM-3/NF-κB regulatory axis in microglial polarization and highlight the targeted inhibition of SPI1 as a promising therapeutic strategy for ameliorating neuroinflammation and halting disease progression in Parkinson’s disease.
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BibTeX
@article{yin2026targeting,
title = {{Targeting the transcription factor SPI1 attenuates neuroinflammation and dopaminergic degeneration in Parkinson’s disease via the tim-3/NF-κb axis}},
author = {Xi Yin and Miao Wang and Yang Gao and Jiarui Yao and Yifan Li and Tong Chen and Zhenfu Wang and Wei Wang and Zhongbao Gao},
journal = {Neurotherapeutics},
year = {2026},
month = oct,
doi = {10.1016/j.neurot.2026.e01106},
url = {https://doi.org/10.1016/j.neurot.2026.e01106},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Targeting the transcription factor SPI1 attenuates neuroinflammation and dopaminergic degeneration in Parkinson’s disease via the tim-3/NF-κb axis
AU - Xi Yin
AU - Miao Wang
AU - Yang Gao
AU - Jiarui Yao
AU - Yifan Li
AU - Tong Chen
AU - Zhenfu Wang
AU - Wei Wang
AU - Zhongbao Gao
PY - 2026
DA - 2026/10/27
JO - Neurotherapeutics
DO - 10.1016/j.neurot.2026.e01106
UR - https://doi.org/10.1016/j.neurot.2026.e01106
AB - Microglia-mediated neuroinflammation is a critical driver of dopaminergic neuronal loss in Parkinson’s disease (PD), presenting a viable target for disease-modifying therapies. Although the transcription factor Spi-1 proto-oncogene (SPI1) is implicated in microglial regulation, its specific pathological role and therapeutic potential in PD remain elusive. In this study, utilizing in vivo MPTP-induced mouse models and in vitro MPP + stimulated microglia, we identified SPI1 as a crucial regulator of PD-associated neuroinflammation. We found that SPI1 expression is aberrantly upregulated in both PD models. Crucially, SPI1 knockdown significantly mitigated motor deficits, attenuated dopaminergic neuronal loss, and suppressed neuroinflammation by reducing proinflammatory cytokines. Mechanistically, we revealed that SPI1 directly binds to the promoter of T-cell immunoglobulin and mucin-domain-containing 3 (TIM-3) to activate its transcription. Silencing SPI1 facilitated a neuroprotective microglial M1-to-M2 phenotypic shift by downregulating TIM-3 and subsequently inhibiting the NF-κB signaling pathway, thereby protecting against synaptic impairment and neuronal apoptosis. Together, our findings elucidate a novel SPI1/TIM-3/NF-κB regulatory axis in microglial polarization and highlight the targeted inhibition of SPI1 as a promising therapeutic strategy for ameliorating neuroinflammation and halting disease progression in Parkinson’s disease.
SN - 1933-7213
SN - 1878-7479
ER -