DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation.
DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation.
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DKK3 通过抑制 ASK-1/JNK/p-38 介导的小胶质细胞极化和神经炎症来改善神经性疼痛
DOI：
10.1186/s12974-022-02495-x
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发表时间：
2022-06-03
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
神经性疼痛是一种常见的严重致残状态，影响着全世界数百万人。脊髓中的小胶质细胞活化在神经病理性疼痛的发病机制中起关键作用。然而，神经病理性疼痛过程中脊髓小胶质细胞激活的机制仍不完全清楚。在这里，我们研究了Dickkopf（DKK）3的作用及其与脊髓中小胶质细胞活化在神经病理性疼痛中的相互作用。在这项研究中，我们研究了鞘内注射重组DKK 3（rDKK 3）对大鼠保留神经损伤（SNI）后的机械异常性疼痛和脊髓小胶质细胞活化的影响，通过蛋白质印迹（WB），免疫荧光（IF），定量聚合酶链反应（qPCR）和酶联免疫吸附试验（ELISA）。结果发现，SNI可显著降低DKK 3、Kremen-1和Dishevelled-1（DVL-1）的表达，上调磷酸化凋亡信号调节激酶1（p-ASK 1）、磷酸化c-JUN N-末端激酶（p-JNK）和磷酸化p38（p-p38）的表达。与SNI + Vehicle组相比，鞘内注射外源性rDKK 3可抑制p-ASK 1、p-JNK、p-p38的表达，促进小胶质细胞由M1型向M2型转化，减少促炎细胞因子的产生。然而，这些作用通过鞘内施用Kremen-1 siRNA或Dishevelled-1（DVL-1）siRNA逆转。这些结果表明，DKK 3通过抑制ASK-1/JNK/p-38介导的小胶质细胞极化和神经炎症，至少部分地通过Kremen-1和DVL-1途径，改善神经性疼痛。在线版本包含补充材料，可通过10.1186/s12974-022-02495-x获得。
Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Microglial activation in the spinal cord plays a critical role in the pathogenesis of neuropathic pain. However, the mechanisms underlying spinal microglial activation during neuropathic pain remain incompletely understood. Here, we investigated the role of Dickkopf (DKK) 3 and its interplay with microglial activation in the spinal cord in neuropathic pain. In this study, we investigated the effects of intrathecal injection of recombinant DKK3 (rDKK3) on mechanical allodynia and microglial activation in the spinal cord after spared nerve injury (SNI) in rats by western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). We found that SNI induced a significant decrease in the levels of DKK3, Kremen-1 and Dishevelled-1 (DVL-1) and up-regulated the expression of phosphorylated apoptosis signal-regulating kinase 1 (p-ASK1), phosphorylated c-JUN N-terminal kinase (p-JNK), phosphorylated p38 (p-p38) in the spinal cord. Moreover, our results showed that exogenous intrathecal administration of rDKK3 inhibited expression of p-ASK1, p-JNK, p-p38, promoted the transformation of microglia from M1 type to M2 type, and decreased the production of pro-inflammatory cytokines compared to the rats of SNI + Vehicle. However, these effects were reversed by intrathecal administration of Kremen-1 siRNA or Dishevelled-1 (DVL-1) siRNA. These results suggest that DKK3 ameliorates neuropathic pain via inhibiting ASK-1/JNK/p-38-mediated microglia polarization and neuroinflammation, at least partly, by the Kremen-1 and DVL-1 pathways. The online version contains supplementary material available at 10.1186/s12974-022-02495-x.
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