DOK3 is involved in microglial cell activation in neuropathic pain by interacting with GPR84

AGING, 2021 · DOI: · Published: December 3, 2020

Simple Explanation

This study investigates the role of DOK3, an adaptor molecule, in microglia-induced neuropathic pain, focusing on its interaction with GPR84. DOK3 is a vital regulator of innate immune responses in macrophages and B cells. GPR84 is significant in mediating the biosynthesis and maintenance of inflammatory mediators induced by neuropathic pain in microglia. The study found that reducing DOK3 levels in microglial cells significantly decreased inflammatory factors. It also uncovered a physical connection between DOK3 and GPR84 in triggering inflammatory responses. Furthermore, neuropathic pain and inflammatory responses caused by nerve injury or a GPR84 agonist were reduced in mice lacking DOK3. The research suggests that targeting DOK3 could provide new ways to develop drugs for alleviating neuropathic pain in the spinal cord. DOK3 induced neuropathic pain in mice by interacting with GPR84 in microglia.

Study Duration

Not specified

Participants

Adult (8-week-old) male B129 mice and DOK3 knockout (KO) mice

Evidence Level

Not specified

Key Findings

1
Knockdown of DOK3 in microglial cells dramatically reduced the levels of inflammatory factors, suggesting that DOK3 regulates the release of a subset of inflammatory mediators in microglia under physiologic conditions.
2
GPR84 activation-induced inflammatory responses are partially mediated via DOK3 in microglia, indicating that DOK3—as a downstream target of the GPR84-signaling pathway—is an important component in immune regulation by microglia.
3
CCI-induced neuropathic pain and inflammatory responses are alleviated in DOK3-/- mice, demonstrating that DOK3 plays a positive role in modulating inflammatory actions and microglial activation in response to peripheral neuropathy.

Research Summary

The study identified a novel role for DOK3 protein in activated microglia-induced neuropathic pain. It induced immune responses and neuropathic pain by a physical interaction with GPR84. Knockdown of DOK3 markedly reduced the levels of inflammatory factors in microglial cells. CCI-induced neuropathic pain was compromised in DOK3-/- mice. Administration of pregabalin was effective in preventing DOK3 upregulation and DOK3 overexpression-induced neuropathic pain in mice, providing additional clinical relevance to the findings.

Practical Implications

Pharmaceutical Approaches

Targeting the adaptor protein DOK3 may open new avenues for pharmaceutical approaches to the alleviation of neuropathic pain in the spinal cord.

Gene Therapy

Targeting the DOK3 gene may in the future constitute a gene-therapy approach to alleviating diseases and injury-induced neuropathic pain in the spinal cord.

Clinical Analgesic Drug Development

Broadened potential application of pregabalin in the improvement of upregulated DOK3-induced neuropathic pain in mice.

Study Limitations

1
The study used male mice, requiring further research on sex differences in pain behavior.
2
Specific binding sites between DOK3 and GPR84 molecules require further elucidation through bioinformatics analyses.
3
Possibility that the signaling complex includes other unknown molecules.

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