SOCS3 ameliorates Parkinson’s disease neuropathology by suppressing NF-κB signaling-mediated microglial inflammation

ZUO Fangya; FENG Dan; LIU Yun; LIU Fenfen; GUO Xiuhong; LIU Yuqi; CHEN Lanlan; WANG Yujie; TIAN Jinyong

doi:10.16016/j.2097-0927.202506029

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SOCS3 ameliorates Parkinson’s disease neuropathology by suppressing NF-κB signaling-mediated microglial inflammation

Neuroscience | 更新时间：2025-11-13

- SOCS3 ameliorates Parkinson’s disease neuropathology by suppressing NF-κB signaling-mediated microglial inflammation
- Journal of Army Medical University Vol. 47, Issue 21, Pages: 2611-2620(2025)
- 作者机构：
  
  1.贵州中医药大学研究生院，贵州贵阳
  2.清镇市第一人民医院重症医学科，贵州贵阳
  3.遵义医科大学研究生院，贵州遵义
  4.贵州省人民医院全科医学科，贵州贵阳
- 作者简介：
  
  TIAN Jinyong， E-mail： tjy8877@163.com
- 基金信息：
  
  the 2020 Major Basic Research Project of Guizhou Provincial Department of Science and Technology （GuiKeHe JiChu［2020］1Z059） and the Scientific and technological Research Project for Traditional Chinese Medicine and Ethnic Medicine of Guizhou Provincial Bureall of Traditional Chinese Medicine(黔科合基础［2020］1Z059);Corresponding author： TIAN Jinyong, E-mail： tjy8877@163.com(QZYY-2021-011)
- DOI：10.16016/j.2097-0927.202506029
  CLC： R364.5;R742.5;R977.6
- Received：10 June 2025，
  
  Revised：2025-10-10，
  
  Accepted：10 October 2025，
  
  Published：15 November 2025
- 稿件说明：
移动端阅览
左方娅，冯丹，刘韵，等.SOCS3通过抑制NF-κB信号通路介导的小胶质细胞炎症反应改善帕金森病神经损伤［J］.陆军军医大学学报，2025，47（21）：2611-2620.DOI：10.16016/j.2097-0927.202506029.

ZUO F Y，FENG D，LIU Y，et al.SOCS3 ameliorates Parkinson’s disease neuropathology by suppressing NF-κB signaling-mediated microglial inflammation［J］.J Army Med Univ，2025，47（21）：2611-2620.DOI：10.16016/j.2097-0927.202506029.
左方娅，冯丹，刘韵，等.SOCS3通过抑制NF-κB信号通路介导的小胶质细胞炎症反应改善帕金森病神经损伤［J］.陆军军医大学学报，2025，47（21）：2611-2620.DOI：10.16016/j.2097-0927.202506029. DOI：

ZUO F Y，FENG D，LIU Y，et al.SOCS3 ameliorates Parkinson’s disease neuropathology by suppressing NF-κB signaling-mediated microglial inflammation［J］.J Army Med Univ，2025，47（21）：2611-2620.DOI：10.16016/j.2097-0927.202506029. DOI：

摘要

目的

探讨细胞因子信号抑制物3（suppressor of cytokine signaling 3，SOCS3）通过核因子-κB（nuclear factor-kappaB，NF-κB）通路调控小胶质细胞炎症反应的作用机制，为帕金森病（Parkinson’s disease，PD）的发病机制提供新见解。

方法

①以10~12周龄C57BL/6雄性小鼠（体质量20~25 g）为造模对象，腹腔注射15 mg/kg 1-甲基-4-苯基-1，2，3，6-四氢吡啶（1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine，MPTP）以建立PD体内模型，采用旋转杆实验评估小鼠运动能力，Western blot法检测小鼠脑黑质区酪氨酸羟化酶（tyrosine hydroxylase，TH）及离子化钙结合衔接分子1（ionized calcium-binding adaptor molecule 1，IBA-1）表达，RT-qPCR检测脑黑质区SOCS3表达，免疫组化检测NF-κB p65亚基表达，Western blot检测SOCS3、NF-κB、p-NF-κB。②对小胶质细胞BV2给予1 000 ng/mL LPS刺激6 h以建立炎性小胶质细胞模型，在此基础上施以敲低SOCS3，并使用BAY 11-7082处理细胞以抑制NF-κB；采用RT-qPCR和Western blot检测BV2细胞SOCS3表达，采用Western blot检测NF-κB和p-NF-κB，ELISA检测细胞培养上清液中TNF-α和IL-1β，免疫荧光定位NF-κB核定位。③建立BV2-脑神经瘤细胞N2a细胞共培养体系探究小胶质细胞对神经细胞的调控作用，采用MTT法检测N2a细胞活性，TUNEL染色检测N2a细胞凋亡。

结果

①相较于对照小鼠，PD小鼠模型表现为旋杆跌落时间缩短，TH和SOCS3下调（

0.01），IBA-1和p-NF-κB/NF-κB比值上调（

0.01）。②在BV2细胞中，LPS刺激导致TNF-α、IL-1β、p-NF-κB/NF-κB比值上调（

0.01），SOCS3下调（

0.01）；在LPS刺激的BV2细胞中，敲低SOCS3导致p-NF-κB/NF-κB比值上调（

0.01），NF-κB多分布于细胞核，TNF-α和IL-1β上调（

0.01）；在此基础上

BAY 11-7082导致p-NF-κB/NF-κB比值、TNF-α、IL-1β下调（

0.01），NF-κB核分布减少。③LPS处理的小胶质细胞导致N2a细胞活性降低（

0.01），并引起细胞凋亡增加（

0.01）；而敲低SOCS3在BV2细胞的表达后，N2a细胞活性降低（

0.01），细胞凋亡增加（

0.01）；在此基础上BAY 11-7082处理小胶质细胞后，N2a细胞活性升高（

0.01），细胞凋亡减少（

0.01）。

结论

SOCS3通过下调NF-κB活性抑制小胶质细胞炎症反应，进而减少神经细胞死亡，改善PD神经损伤。

Abstract

Objective

To investigate the mechanism by which suppressor of cytokine signaling 3 (SOCS3) regulates microglial inflammation through nuclear factor-kappaB (NF-κB)

providing novel mechanistic insights into microglial involvement in Parkinson’s disease (PD) pathogenesis.

Methods

① Ten male C57BL/6 mice (12 weeks old

weighing 20~25 g) were subjected to intraperitoneal injection of 15 mg/kg MPTP to establish a PD model. Rotarod test was used to assess motor function. Western blotting was employed to detect the protein expression of tyrosine hydroxylase (TH) and ionized calcium-binding adapter molecule 1 (IBA-1) in the substantia nigra. RT-qPCR was utilized to measure the mRNA level of SOCS3 in the substantia nigra. Immunohistochemistry was performed to assess NF-κB p65 subunit expression. The expression of SOCS3

NF-κB and p-NF-κB was measured with Western blotting. ② Microglial cell line BV2 was stimulated with 1 000 ng/mL lipopolysaccharide (LPS) for 6 h to establish an inflammatory model. Subsequently

SOCS3 was knocked down. NF-κB inhibitor BAY 11-7082 was used to treat the cells. RT-qPCR and Western blotting were used to measure the expression of SOCS3 at mRNA and protein levels. Western blotting was also applied to detect the expression of NF-κB and p-NF-κB

and ELISA was conducted to measure TNF-α and IL-1β levels in the culture supernatant. Immunofluorescence assay was carried out to localize NF-κB (nuclear

cytoplasmic). ③

A co-culture system of BV2 microglia and N2a neuroblastoma cells was established to investigate the regulatory effects of microglia on neuronal cells. MTT assay and TUNEL staining were used respectively to determine cell viability and apoptosis of N2a cells.

Results

① Compared to the control mice

the PD mouse model exhibited reduced rotarod fall latency

down-regulation in TH and SOCS3(

0.01)

up-regulation in IBA-1 and increased p-NF-κB/NF-κB ratio (

0.01). ② In BV2 cells

LPS stimulation increased TNF-α

IL-1β

and p-NF-κB/NF-κB ratio(

0.01)

while down-regulated SOCS3 expression(

0.01). SOCS3 knockdown in LPS-stimulated BV2 cells further increased the p-NF-κB/NF-κB ratio (

0.01)

increased nuclear localization of NF-κB

and elevated TNF-α and IL-1β levels (

0.01). BAY 11-7082 treatment in these SOCS3-knockdown

LPS-stimulated cells resulted in reduced p-NF-κB/NF-κB ratio

TNF-α

and IL-1β (

0.01)

and decreased NF-κB nuclear distribution. ③ LPS-stimulated BV2 cells reduced cell viability and increased cell apoptosis in N2a cells(

0.01). SOCS3 knockdown in BV2 cells exacerbated the reduction in N2a cell viability (

0.01) and the increase in cell apoptosis in N2a cells (

0.01). BAY 11-7082 treatment of these SOCS3-knockdown BV2 microglia attenuated the reduction in N2a cell viability and decreased apoptosis in N2a cells (

0.01).

Conclusion

SOCS3 inhibits microglia inflammatory response through down-regulation of NF-kB activity

and in turn attenuates neuronal cell death and ameliorates PD nerve injury.

关键词

Keywords

references

LIU T W ， CHEN C M ， CHANG K H . Biomarker of neuroinflammation in Parkinson’s disease ［J］. Int J Mol Sci ， 2022 ， 23 （ 8 ）： 4148 . DOI： 10.3390/ijms23084148 http://dx.doi.org/10.3390/ijms23084148 .

SIMON D K ， TANNER C M ， BRUNDIN P . Parkinso’s disease epidemiology， pathology， genetics， and pathophysio-logy ［J］. Clin Geriatr Med ， 2020 ， 36 （ 1 ）： 1 - 12 . DOI： 10.1016/j.cger.2019.08.002 http://dx.doi.org/10.1016/j.cger.2019.08.002 .

BLOEM B R ， OKUN M S ， KLEIN C . Parkinson’s disease ［J］. Lancet ， 2021 ， 397 （ 10291 ）： 2284 - 2303 . DOI： 10.1016/S0140-6736（21）00218-X http://dx.doi.org/10.1016/S0140-6736（21）00218-X .

YE H ， ROBAK L A ， YU M G ， et al . Genetics and pathogenesis of Parkinson’s syndrome ［J］. Annu Rev Pathol ， 2023 ， 18 ： 95 - 121 . DOI： 10.1146/annurev-pathmechdis-031521-034145 http://dx.doi.org/10.1146/annurev-pathmechdis-031521-034145 .

刘旺，赵虹，夏兆云，等 . 帕金森病相关病理演变研究进展［J］. 神经损伤功能重建， 2022 ， 17 （ 3 ）： 148 - 151 . DOI： 10.16780/j.cnki.sjssgncj.20200807 http://dx.doi.org/10.16780/j.cnki.sjssgncj.20200807 .

LIU W ， ZHAO H ， XIA Z Y ， et al . Research advances in the pathological progression of Parkinson’s disease ［J］. Neural Inj Funct Reconstr ， 2022 ， 17 （ 3 ）： 148 - 151 . DOI： 10.16780/j.cnki.sjssgncj.20200807 http://dx.doi.org/10.16780/j.cnki.sjssgncj.20200807 .

BORST K ， DUMAS A A ， PRINZ M . Microglia： immune and non-immune functions ［J］. Immunity ， 2021 ， 54 （ 10 ）： 2194 - 2208 . DOI： 10.1016/j.immuni.2021.09.014 http://dx.doi.org/10.1016/j.immuni.2021.09.014 .

ZHANG L J ， CAO Y ， ZHANG X ， et al . The origin and repopulation of microglia ［J］. Dev Neurobiol ， 2022 ， 82 （ 1 ）： 112 - 124 . DOI： 10.1002/dneu.22862 http://dx.doi.org/10.1002/dneu.22862 .

STEFANOVA N . Microglia in Parkinson’s disease ［J］. J Parkinsons Dis ， 2022 ， 12 （ s1 ）： S105 - S112 . DOI： 10.3233/JPD-223237 http://dx.doi.org/10.3233/JPD-223237 .

BADANJAK K ， FIXEMER S ， SMAJIĆ S ， et al . The contribution of microglia to neuroinflammation in Parkinson’s disease ［J］. Int J Mol Sci ， 2021 ， 22 （ 9 ）： 4676 . DOI： 10.3390/ijms22094676 http://dx.doi.org/10.3390/ijms22094676 .

刘玥滢，杜天舒，刘玚，等 . 小胶质细胞介导的吞噬作用在神经退行性疾病中的研究进展［J］. 生理学报， 2022 ， 74 （ 2 ）： 283 - 293 . DOI： 10.13294/j.aps.2022.0031 http://dx.doi.org/10.13294/j.aps.2022.0031 .

LIU Y Y ， DU T S ， LIU Y ， et al . Phagocytosis of microglia in neurodegenerative diseases ［J］. Acta Physiol Sin ， 2022 ， 74 （ 2 ）： 283 - 293 . DOI： 10.13294/j.aps.2022.0031 http://dx.doi.org/10.13294/j.aps.2022.0031 .

RABIE M A ， ABD EL FATTAH M A ， NASSAR N N ， et al . Correlation between angiotensin 1-7-mediated Mas receptor expression with motor improvement， activated STAT3/SOCS3 cascade， and suppressed HMGB-1/RAGE/NF-κB signaling in 6-hydroxydopamine hemiparkinsonian rats ［J］. Biochem Pharmacol ， 2020 ， 171 ： 113681 . DOI： 10.1016/j.bcp.2019.113681 http://dx.doi.org/10.1016/j.bcp.2019.113681 .

YU H ， LIN L ， ZHANG Z ， et al . Targeting NF-κB pathway for the therapy of diseases： mechanism and clinical study ［J］. Signal Transduct Target Ther ， 2020 ， 5 （ 1 ）： 209 . DOI： 10.1038/s41392-020-00312-6 http://dx.doi.org/10.1038/s41392-020-00312-6 .

WILLIAMS L M ， GILMORE T D . Looking down on NF-κB ［J］. Mol Cell Biol ， 2020 ， 40 （ 15 ）： e00104-20 . DOI： 10.1128/mcb.00104-20 http://dx.doi.org/10.1128/mcb.00104-20 .

POMA P . NF-κB and disease ［J］. Int J Mol Sci ， 2020 ， 21 （ 23 ）： E9181 . DOI： 10.3390/ijms21239181 http://dx.doi.org/10.3390/ijms21239181 .

LI Y N ， XIA Y ， YIN S J ， et al . Targeting microglial α-synuclein/TLRs/NF-kappaB/NLRP3 inflammasome axis in Parkinson’s disease ［J］. Front Immunol ， 2021 ， 12 ： 719807 . DOI： 10.3389/fimmu.2021.719807 http://dx.doi.org/10.3389/fimmu.2021.719807 .

IWAHARA N ， HISAHARA S ， KAWAMATA J ， et al . Role of suppressor of cytokine signaling 3 （SOCS3） in altering activated microglia phenotype in APPswe/PS1dE9 mice ［J］. J Alzheimers Dis ， 2017 ， 55 （ 3 ）： 1235 - 1247 . DOI： 10.3233/JAD-160887 http://dx.doi.org/10.3233/JAD-160887 .

CAI L J ， TU L ， HUANG X M ， et al . LncRNA MALAT1 facilitates inflammasome activation via epigenetic suppression of Nrf2 in Parkinson’s disease ［J］. Mol Brain ， 2020 ， 13 （ 1 ）： 130 . DOI： 10.1186/s13041-020-00656-8 http://dx.doi.org/10.1186/s13041-020-00656-8 .

QIU J R ， CHEN Y ， ZHUO J ， et al . Urolithin A promotes mitophagy and suppresses NLRP3 inflammasome activation in lipopolysaccharide-induced BV2 microglial cells and MPTP-induced Parkinson’s disease model ［J］. Neuropharmacology ， 2022 ， 207 ： 108963 . DOI： 10.1016/j.neuropharm.2022.108963 http://dx.doi.org/10.1016/j.neuropharm.2022.108963 .

CAI M Y ， ZHUANG W X ， LV E ， et al . Kaemperfol alleviates pyroptosis and microglia-mediated neuroin-flammation in Parkinson’s disease via inhibiting p38MAPK/NF-κB signaling pathway ［J］. Neurochem Int ， 2022 ， 152 ： 105221 . DOI： 10.1016/j.neuint.2021.105221 http://dx.doi.org/10.1016/j.neuint.2021.105221 .

ZHENG Y ， HOU X H ， YANG S B . Lidocaine potentiates SOCS3 to attenuate inflammation in microglia and suppress neuropathic pain ［J］. Cell Mol Neurobiol ， 2019 ， 39 （ 8 ）： 1081 - 1092 . DOI： 10.1007/s10571-019-00703-6 http://dx.doi.org/10.1007/s10571-019-00703-6 .

LIU Y ， LIAO S J ， BENNETT S ， et al . STAT3 and its targeting inhibitors in osteosarcoma ［J］. Cell Prolif ， 2021 ， 54 （ 2 ）： e12974 . DOI： 10.1111/cpr.12974 http://dx.doi.org/10.1111/cpr.12974 .

GRIVENNIKOV S I ， KARIN M . Dangerous liaisons： STAT3 and NF-kappaB collaboration and crosstalk in cancer ［J］. Cytokine Growth Factor Rev ， 2010 ， 21 （ 1 ）： 11 - 19 . DOI： 10.1016/j.cytogfr.2009.11.005 http://dx.doi.org/10.1016/j.cytogfr.2009.11.005 .

CROKER B A ， KREBS D L ， ZHANG J G ， et al . SOCS3 negatively regulates IL-6 signaling in vivo ［J］. Nat Immunol ， 2003 ， 4 （ 6 ）： 540 - 545 . DOI： 10.1038/ni931 http://dx.doi.org/10.1038/ni931 .

AOKI H ， MAJIMA R ， HASHIMOTO Y ， et al . Ying and Yang of Stat3 in pathogenesis of aortic dissection ［J］. J Cardiol ， 2021 ， 77 （ 5 ）： 471 - 474 . DOI： 10.1016/j.jjcc.2020.10.010 http://dx.doi.org/10.1016/j.jjcc.2020.10.010 .

MCGREGOR N E ， WALKER E C ， CHAN A S ， et al . STAT3 hyperactivation due to SOCS3 deletion in murine osteocytes accentuates responses to exercise- and load-induced bone formation ［J］. J Bone Miner Res ， 2022 ， 37 （ 3 ）： 547 - 558 . DOI： 10.1002/jbmr.4484 http://dx.doi.org/10.1002/jbmr.4484 .

WALKER E C ， TRUONG K ， MCGREGOR N E ， et al . Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes ［J］. eLife ， 2020 ， 9 ： e56666 . DOI： 10.7554/eLife.56666 http://dx.doi.org/10.7554/eLife.56666 .

BARNABEI L ， LAPLANTINE E ， MBONGO W ， et al . NF-κB： at the borders of autoimmunity and inflammation ［J］. Front Immunol ， 2021 ， 12 ： 716469 . DOI： 10.3389/fimmu. 2021. 716469 http://dx.doi.org/10.3389/fimmu.2021.716469 .

WOODBURN S C ， BOLLINGER J L ， WOHLEB E S . The semantics of microglia activation： neuroinflammation， homeostasis， and stress ［J］. J Neuroinflammation ， 2021 ， 18 （ 1 ）： 258 . DOI： 10.1186/s12974-021-02309-6 http://dx.doi.org/10.1186/s12974-021-02309-6 .

GODDERY E N ， FAIN C E ， LIPOVSKY C G ， et al . Microglia and perivascular macrophages act as antigen presenting cells to promote CD8 T cell infiltration of the brain ［J］. Front Immunol ， 2021 ， 12 ： 726421 . DOI： 10.3389/fimmu.2021.726421 http://dx.doi.org/10.3389/fimmu.2021.726421 .

王泽泽，杨学森，王英，等 . 热习服对电磁辐射所致小鼠海马神经损伤的保护作用及机制研究［J］. 陆军军医大学学报， 2025 ， 47 （ 7 ）： 629 - 638 . DOI： 10.16016/j.2097-0927.202408087 http://dx.doi.org/10.16016/j.2097-0927.202408087 .

WANG Z Z ， YANG X S ， WANG Y ， et al . Protective effect and mechanism of heat acclimation on hippocampus neuron injury in mice after exposure to electromagnetic field ［J］. J Amry Med Univ ， 2025 ， 47 （ 7 ）： 629 - 638 . DOI： 10.16016/j.2097-0927.202408087 http://dx.doi.org/10.16016/j.2097-0927.202408087 .

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