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Journal of neuroinflammation
Jun 03, 2022;19 (1): 129.

DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation.

Long-Qing Zhang, Shao-Jie Gao, Jia Sun, Dan-Yang Li, Jia-Yi Wu, Fan-He Song, Dai-Qiang Liu, Ya-Qun Zhou, Wei Mei
Author Information
  1. Long-Qing Zhang: Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
  2. Shao-Jie Gao: Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
  3. Jia Sun: Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
  4. Dan-Yang Li: Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
  5. Jia-Yi Wu: Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
  6. Fan-He Song: Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
  7. Dai-Qiang Liu: Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China.
  8. Ya-Qun Zhou: Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China. yqzhou2019@hust.edu.cn.
  9. Wei Mei: Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji MedicalCollege, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People's Republic of China. wmei@hust.edu.cn.
PMID: 35658977 DOI: 10.1186/s12974-022-02495-x

Abstract

BACKGROUND: Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Microglial activation in the spinal cord plays a critical role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely understood. Here, we investigated the role of Dickkopf (DKK) 3 and its interplay with microglial activation in the spinal cord in neuropathic pain.
METHODS: In this study, we investigated the effects of intrathecal injection of recombinant DKK3 (rDKK3) on mechanical allodynia and microglial activation in the spinal cord after spared nerve injury (SNI) in rats by western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA).
RESULTS: We found that SNI induced a significant decrease in the levels of DKK3, Kremen-1 and Dishevelled-1 (DVL-1) and up-regulated the expression of phosphorylated apoptosis signal-regulating kinase 1 (p-ASK1), phosphorylated c-JUN N-terminal kinase (p-JNK), phosphorylated p38 (p-p38) in the spinal cord. Moreover, our results showed that exogenous intrathecal administration of rDKK3 inhibited expression of p-ASK1, p-JNK, p-p38, promoted the transformation of microglia from M1 type to M2 type, and decreased the production of pro-inflammatory cytokines compared to the rats of SNI + Vehicle. However, these effects were reversed by intrathecal administration of Kremen-1 siRNA or Dishevelled-1 (DVL-1) siRNA.
CONCLUSIONS: These results suggest that DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation, at least partly, by the Kremen-1 and DVL-1 pathways.

Keywords

DKK3 Microglial polarization Neuroinflammation Neuropathic pain

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Grants

  1. 82101310/National Natural Science Foundation of China
  2. 82001198/National Natural Science Foundation of China
  3. 82071556/National Natural Science Foundation of China
  4. 81873793/National Natural Science Foundation of China
  5. 2020YFC2005300/National Key Research and Development Program of China

MeSH Term

Adaptor Proteins, Signal Transducing
Animals
Hyperalgesia
Intercellular Signaling Peptides and Proteins
Microglia
Neuralgia
Neuroinflammatory Diseases
RNA, Small Interfering
Rats
Spinal Cord

Chemicals

Adaptor Proteins, Signal Transducing
Dkk3 protein, rat
Intercellular Signaling Peptides and Proteins
RNA, Small Interfering
Journal Article

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