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Featured ArticleResearch Articles, Cellular/Molecular

Fibroblastic SMOC2 Suppresses Mechanical Nociception by Inhibiting Coupled Activation of Primary Sensory Neurons

Shuo Zhang, Bing Cai, Zhen Li, Kaikai Wang, Lan Bao, Changlin Li and Xu Zhang
Journal of Neuroscience 18 May 2022, 42 (20) 4069-4086; DOI: https://doi.org/10.1523/JNEUROSCI.2132-21.2022
Shuo Zhang
1Institute of Neuroscience and State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
2School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
3Research Unit of Pain Medicine, Chinese Academy of Medical Sciences; and SIMR Joint Lab of Drug Innovation, Shanghai Advanced Research Institute, Chinese Academy of Sciences; Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China
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Bing Cai
3Research Unit of Pain Medicine, Chinese Academy of Medical Sciences; and SIMR Joint Lab of Drug Innovation, Shanghai Advanced Research Institute, Chinese Academy of Sciences; Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China
4Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, 519031, China
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Zhen Li
3Research Unit of Pain Medicine, Chinese Academy of Medical Sciences; and SIMR Joint Lab of Drug Innovation, Shanghai Advanced Research Institute, Chinese Academy of Sciences; Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China
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Kaikai Wang
1Institute of Neuroscience and State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
2School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
3Research Unit of Pain Medicine, Chinese Academy of Medical Sciences; and SIMR Joint Lab of Drug Innovation, Shanghai Advanced Research Institute, Chinese Academy of Sciences; Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China
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Lan Bao
2School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
5State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China
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Changlin Li
3Research Unit of Pain Medicine, Chinese Academy of Medical Sciences; and SIMR Joint Lab of Drug Innovation, Shanghai Advanced Research Institute, Chinese Academy of Sciences; Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China
4Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, 519031, China
6Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518060, China
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Xu Zhang
1Institute of Neuroscience and State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
2School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
3Research Unit of Pain Medicine, Chinese Academy of Medical Sciences; and SIMR Joint Lab of Drug Innovation, Shanghai Advanced Research Institute, Chinese Academy of Sciences; Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, 201210, China
4Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, 519031, China
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Abstract

Nociceptive information is detected and transmitted by neurons in the DRG. Recently, single-cell RNA sequencing has revealed the molecular profile of various cell types, including fibroblasts in the DRG. However, the role of molecules in fibroblasts needs to be elucidated in nociceptive regulation. Here, we found that secreted modular calcium-binding protein 2 (SMOC2) was secreted by fibroblasts to become a component of basement membrane and envelop the unit consisting of DRG neurons and attached satellite glial cells. KO of Smoc2 in both sexes of mice led to increased neuronal clusters and decreased mechanical threshold, but unchanged noxious thermal response. Knockdown of Smoc2 in the DRG phenocopied the behavioral performance by Smoc2 KO in both sexes of mice. In vivo calcium imaging showed that Smoc2 KO increased coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli, which was reversed by DRG injection of SMOC2. Importantly, SMOC2 interacted with P2X7 receptor (P2X7R) and suppressed ATP-induced activation in HEK293 cells expressing this receptor. Injection of A740003, an antagonist of P2X7R, to the DRG reduced coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli but did not further enhance the SMOC2-inhibited effect. Furthermore, peripheral inflammation resulted in a decreased SMOC2 and increased neuronal clusters. DRG injection of SMOC2 inhibited the neuronal coupling resulted from peripheral inflammation. This study reveals a specific role of fibroblastic SMOC2 in suppressing mechanical nociception through inhibiting the communication of adjacent DRG neurons, which provides an important mechanism of fibroblasts in nociceptive regulation.

SIGNIFICANCE STATEMENT The function of fibroblastic molecules is rarely noticed in the regulation of nociceptive sensation. Here, we reveal that fibroblastic SMOC2 is secreted to be a component of basement membrane and surrounded the unit consisting of DRG neuron and attached satellite glial cells. SMOC2 is required for maintaining the basal mechanical nociceptive threshold in the DRG. Loss of SMOC2 leads to the increased coupled activation of adjacent DRG neurons induced by noxious mechanical stimuli. Peripheral inflammation causes decreased fibroblast cells and SMOC2, which may result in the increase of coupled activation of adjacent DRG neurons. Mechanistically, SMOC2 interacts with and suppresses satellite glial P2X7 receptor to inhibit the coupled activation of adjacent DRG neurons.

  • DRG
  • fibroblast
  • mechanical nociception
  • SMOC2

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The Journal of Neuroscience: 42 (20)
Journal of Neuroscience
Vol. 42, Issue 20
18 May 2022
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Fibroblastic SMOC2 Suppresses Mechanical Nociception by Inhibiting Coupled Activation of Primary Sensory Neurons
Shuo Zhang, Bing Cai, Zhen Li, Kaikai Wang, Lan Bao, Changlin Li, Xu Zhang
Journal of Neuroscience 18 May 2022, 42 (20) 4069-4086; DOI: 10.1523/JNEUROSCI.2132-21.2022

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Fibroblastic SMOC2 Suppresses Mechanical Nociception by Inhibiting Coupled Activation of Primary Sensory Neurons
Shuo Zhang, Bing Cai, Zhen Li, Kaikai Wang, Lan Bao, Changlin Li, Xu Zhang
Journal of Neuroscience 18 May 2022, 42 (20) 4069-4086; DOI: 10.1523/JNEUROSCI.2132-21.2022
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Keywords

  • DRG
  • fibroblast
  • mechanical nociception
  • SMOC2

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