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

Abstract

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.

Comprehensive analysis of Downstream of Kinase (DOK) Genes in Pan-cancer

“…Then, tumor samples were classi ed according to different immune subtypes of C1-C6 ( 9), and the expression levels of DOK1-DOK7 RNA-seq were statistically analyzed, and the results showed that these genes were signi cantly correlated with the immunotyping. As previously reported, DOK3 is an important modulator of innate immune responses in macrophages and B cells and modulates downstream signaling pathways of various immune receptors (22,23). DOK1 is a tumor suppressor that is often lost in malignant cells, but it still regulates the immunoreceptor activity of stromal cells in the tumor microenvironment and promotes the invasion of cancer cells (24,25).…”

RIP3 Inhibition ameliorates chronic constriction injury-induced neuropathic pain by suppressing JNK signaling

“…In the central nervous system, microglia monitor the local environment to respond quickly to a wide range of inflammatory stimuli, while astrocytes function as immune response cells to produce a large number of inflammatory mediators [ 6 , 33 ]. To evaluate the effects of RIP3 and JNK inhibitors on the density of glial cells and the activation of microglia and astrocytes in vivo , we stained for the astrocyte-specific marker glial fibrillary acidic protein (GFAP) and the microglia- specific marker ionized calcium-binding adaptor molecule 1 (IBA-1).…”

Alzheimer’s disease: insights from a network medicine perspective

“…In particular, HCK is a hematopoietic cell kinase whose dysregulation may affect microglia (i.e., resident immune cells in the central nervous system playing critical roles in brain immunity, development, and homeostasis) and accelerate early stage Alzheimer's disease-like neuropathology 46 . Recently, also the colony stimulating factor 3 receptor (CSF3R) and the docking protein 3 (DOK3) was found to be involved in the in microglial cell activation 47 , 48 .…”