J Neuroinflammation—Chen Gang's research group revealed that Schwann cell Pannexin 1 regulates neuropathic pain by mediating inflammatory responses

Written by - Wei Zhongya Responsible Editor - Wang Sizhen Editor - Xia Ye Neuropathological pain is pathological pain
caused by nerve damage or related diseases.
Because of its relatively complex pathogenesis, it is still a major challenge
in clinical treatment.
However, the study of neuropathic pain mechanisms has focused on neurons, including the activation of primary sensory neurons and the imbalance
between excitatory and inhibitory synaptic transmission in the central nervous system.
With the deepening of research, more and more research has found that non-neuronal cells, especially glial cells, play a non-negligible role in regulating neuropathic pain [1-3
].
Of these, the vast majority of research has focused on glial cells at the central nervous system and spinal cord level [4-6], while the role of Schwann cells in the peripheral nervous system in regulating neuropathic pain is not entirely clear
.

On October 4, 2022, the Chen Gang Research Group of the Key Laboratory of Neuroregeneration at Nantong University published a report in the Journal of Neuroinflammation titled "Inhibition of Schwann cell pannexin 1 attenuates neuropathic pain through the suppression of inflammatory.
" The responses research paper enriches our understanding of Panx 1's involvement in neuropathic pain regulation, provides a fundamental theoretical basis for its use as a therapeutic target, and also reveals the important role
of Schwann cells in neuropathic pain regulation 。 The authors found that chronic constriction injury (CCI)-induced neuropathic pain caused a sustained inflammatory response and upregulation of the expression of Schwann cell Pannexin 1 (Panx 1), and inhibited the expression or activity of Schwann cell Panx 1 through pharmacology and virus-mediated gene manipulation, which can significantly alleviate CCI-induced neuropathic pain
。 Further studies have shown that inhibition of Panx 1 can effectively alleviate the inflammatory response process simulated by LPS stimulation of Schwann cells, which relies on the expression of Schwann cell Panx 1 and the activity
of the channel.


Pannexins are a half-channel membrane protein that is highly permeable to ATP
.
The family consists of three main members, Panx 1, Panx 2, and Panx 3, with Panx 1 being the most widely distributed in the nervous system, including neurons and glial cells.
[7]
Studies have shown that the activation of Panx 1 in the brain, involved in the pathological processes of epilepsy and headache; During the development of neuropathic pain, the activation of Panx 1 in dorsal root ganglion (DRG), astrocytes and microglia all play a regulatory role [8-10].

At the same time, our previous studies showed that Schwann cells primarily express Panx 1 compared to the other two family members, and inhibition of Panx 1 significantly reduces hypotonic induced ATP release [11].

However, the role of Schwann cell Panx 1 in neuropathic pain remains unclear
.

In this study, the authors used chronic compressive injury (CCI) to simulate neuropathic pain by submetrial injection of Panx 1 inhibitors CBX, probenecid, and mimic inhibitory peptide ¹⁰ Panx inhibits the function of Panx 1 and can effectively alleviate CCI-induced mechanical pain and hyperalgesia (Figure 1A-D); Interestingly, the mouse CCI model was followed by subneural injection of probenecid, which significantly inhibited the expression of Panx 1 in Schwann cells, but had no significant effect on the expression of Panx 1 in DRG (Figure 1E-H).

。 Considering that Panx 1 is expressed in DRG, satellite cells, and macrophages, the authors used Panx 1-shRNA to construct Cre-dependent LoxP virus, pAAV-CBG-Dio-EGFP-miR30shRNA (Panx 1)-WPRE(shRNA-Panx 1-AAV) binding to P0-Cre transgenic mice specific knockdown Schwann cell Panx 1 expression (Figure 2C-D), A similar effect is produced (Figures 2A-B
).
These in vivo results suggest that pharmacological or genetically manipulated inhibition of the function of Schwann cell Panx 1 significantly relieves CCI-induced neuropathic pain
.

Figure 1 Panx 1 function blocker can effectively relieve CCI-induced mechanical pain and hypersensitivity to thermal pain (Source: Wang Q, et al.
, J Neuroinflammation, 2022)
Figure 2 Specific knockout Schwann cell Panx 1 can relieve CCI-induced mechanical pain and hyperalgesia (Source: Wang Q, et al.
, J Neuroinflammation, 2022) Because nerve damage is often accompanied by a persistent inflammatory response, researchers use lipopolysaccharides (LPS)
as stimuli to stimulate primary cultured Schwann cells to construct an in vitro model of inflammation
。 In addition to using the Panx 1 inhibitor CBX, the authors also used Panx 1-siRNA to inhibit the expression of Schwann cells, and by detecting the expression and release of inflammatory related factors, it was finally confirmed that inhibiting the expression or function of Panx 1 in Schwann cells significantly alleviated the LPS-induced inflammatory microenvironment (Figure 3).

After ruling out that LPS stimulation had no significant effect on Schwann cell expression, the authors further explored the role
of Panx 1 channel activity in this process using ethidium bromide (EB) ingestion experiments.
Finally, in vitro experiments confirmed that the LPS stimulus-induced inflammatory response process depends on the activity of the Panx 1 channel and its expression
.
Fig.
3 Both CBX and Panx 1-siRNA significantly inhibit LPS-induced inflammatory response (Source: Wang Q, et al.
, J Neuroinflammation, 2022) Picture 4 Inhibition of Panx 1 channel activity and expression can significantly downregulate the uptake of EB by LPS-induced Schwann cells (Source: Wang Q, et al.
, J Neuroinflammation, 2022)

Conclusion and discussion, inspiration and prospect This study revealed through in vivo and in vivo experiments that the inflammatory response mediated by Schwann cell Panx 1 is involved in the regulation
of neuropathic pain.
Inhibition of the function and expression of Schwann cell Panx 1 for the relief of neuropathic pain induced by chronic compressive injury (CCI); At the same time, it can inhibit the Schwann cell inflammatory response induced by LPS in vitro; This process depends on the activity of the Panx 1 channel and its expression
.
The interaction of Panx 1 with P2X7 receptors plays a crucial role
in pain perception in the peripheral and central nervous systems.
Therefore, in neuropathic pain, it is worth further exploration
whether the P2X7 receptor serves as a key player in the Schwann cell Panx 1 signaling pathway 。 In addition, at present, although toll-like receptors are known to be highly expressed in Schwann cells, how LPS-treated Schwann cells release cytokines and chemokines and interact with receptors of their surrounding cells (neurons, monocytes, and macrophages) (e.
g.
, IL-1/IL1R, IL6/IL-6R, CCL2/CCR2, and CXCL1/CXCR2) and their underlying molecular mechanisms in neuropathic pain deserve further study
。 Original link: https://jneuroinflammation.
biomedcentral.
com/articles/10.
1186/s12974-022-02603-x

Qian Wang of the Key Laboratory of Neuroregeneration of Nantong University is the first author of the paper, and Professor Chen Gang and Associate Professor Wei Zhongya are the co-corresponding authors
of the paper.

Wang Qian (left), Chen Gang (middle), Wei Zhongya (right) (photo provided by: Chen Gang/Wei Zhongya team at Nantong University)
Selected articles from previous issues

[1] The NPP-Luo Xiongjian research group used Mendelian randomization to screen potential drug targets for the treatment of mental illness

[2] Adv Sci-Chai Renjie's team made important progress in the regeneration of functional hair cells in cochlear organs

[3] J Neuroinflammation—Tang Yamei's team discovered the mechanism by which pregabalin mitigates microglial activation and neuronal damage in radioactive brain injury

[4] Transl Psychiatry—Accelerated aging of brain function in patients with major depression: evidence from large Chinese participants

[5] Nat Commun—Xu Tianle/Li Weiguang/Zhang Siyu teamwork reveals the neuronal cluster organization of fear and regression memory competition

[6] The Brain-Yi Chenju/Niu Jianqin team found that activating the Wnt/β-catenin pathway could alleviate the blood-brain barrier dysfunction in Alzheimer's disease

[7] Prog Neurobiol Frontier ThinkingEffects of genetic factors, aging and intestinal microbial disorders on immune responses in "dry" and "wet" retinal degeneration

[8] Sci Adv-Xi Zhengxiong's team discovered a new mechanism of sports reward: the midbrain red nucleus-ventral covered area glutamate neural pathway

[9] Mol Psychiatry—Jianqin Niu/Lan Xiao's team found that the variable shearing of oligodendroglial precursor cells DISC-Δ3 inhibits excitatory synaptic growth leading to schizophrenia

【10】PNAS | Sun Bo's research group and collaborators found that time signaling is the main factor in regulating multicellular information networks

Recommended high-quality scientific research training courses[1] Seminar on Single Cell Sequencing and Spatial Transcriptomics Data Analysis (October 29-30, Tencent Online Conference)【2】Seminar on Patch Clamp and Optogenetics and Calcium Imaging Technology (October 15-16, 2022, Tencent Conference) Conference/Forum Preview & Review

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