Research Paper Volume 13, Issue 1 pp 389—410
DOK3 is involved in microglial cell activation in neuropathic pain by interacting with GPR84
- 1 Rehabilitation Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
Received: June 25, 2020 Accepted: September 9, 2020 Published: December 3, 2020https://doi.org/10.18632/aging.202144
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Copyright: © 2020 Gao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Adaptor molecule downstream of kinase-3 (DOK3) is a vital regulator of innate immune responses in macrophages and B cells, and G-protein-coupled receptor 84 (GPR84) is significant in mediating the biosynthesis and maintenance of inflammatory mediators that are induced by neuropathic pain in microglia. In the present study, we determined the role of DOK3 in activating microglia-induced neuropathic pain and investigated the underlying mechanisms associated with GPR84. We found that knockdown of DOK3 in microglial cells dramatically reduced the levels of inflammatory factors, and we uncovered a physical association between DOK3 and GPR84 in the induction of inflammatory responses. We also observed that neuropathic pain and inflammatory responses induced by chronic constriction injury (CCI) of the sciatic nerve or intrathecal injection of a GPR84 agonist were compromised in DOK3-/- mice in vivo. Finally, enforced expression of DOK3 provoked inflammatory responses, and administration of pregabalin relieved neuropathic pain via inhibition of DOK3 expression. In conclusion, DOK3 induced neuropathic pain in mice by interacting with GPR84 in microglia. We hypothesize that targeting the adaptor protein DOK3 may open new avenues for pharmaceutical approaches to the alleviation of neuropathic pain in the spinal cord.
DOK3: downstream of kinase-3; GPR84: G-protein-coupled receptor 84; CNS: central nervous system; MAPKs: mitogen-activated protein kinases; SAP: synapse-associated proteins; PCs: plasma cells; shRNA: short hairpin RNA; Arg1: arginase-1; 6-OAU: 6-n-octylaminouracil; Iba-1: ionized calcium-binding adapter molecule-1; IP: immunoprecipitation; WCL: whole microglial cell lysates; GST: glutathione S-transferase; IFC: immunofluorescence; NFAT: nuclear factor of activated T-cells; KO: knockout; CCI: chronic constriction injury of the sciatic nerve; PWMT: paw-withdrawal mechanical threshold; PWL: paw withdrawal latency.