Activation of microglial GPR109A alleviates thermal hyperalgesia in female lupus mice by suppressing IL-18 and glutamatergic synaptic activity.
Activation of microglial GPR109A alleviates thermal hyperalgesia in female lupus mice by suppressing IL-18 and glutamatergic synaptic activity.
复制标题
DOI：
10.1002/glia.24130
复制
发表时间：
2022-04
期刊：
影响因子：
6.2
通讯作者：
Weng, Han-Rong
中科院分区：
文献类型：
--
作者：
Viatchenko-Karpinski, Viacheslav;Kong, Lingwei;Weng, Han-Rong
尽管医疗管理在降低 SLE 相关死亡率方面取得了进步，但许多系统性红斑狼疮 (SLE) 患者仍患有慢性疼痛。很少有动物研究涉及 SLE 引起的慢性疼痛的机制和治疗。在这项研究中，我们为 GPR109A 特异性激动剂 (MK1903) 的镇痛作用及其在雌性 MRL/lpr 小鼠（一种 SLE 小鼠模型）热痛觉过敏中的作用机制提供了第一个证据。具体来说，我们发现 MRL/lpr 小鼠在 11-16 周龄时对热刺激具有更高的敏感性，同时伴有显着的小胶质细胞和星形胶质细胞激活、p38 MAPK 和脊髓背角谷氨酸突触活动的增加。我们证明，鞘内注射 MK1903 可以显着减弱 MRL/lpr 小鼠的热痛觉过敏。 GPR109A 在脊髓小胶质细胞中表达，但在星形胶质细胞或神经元中不表达。在热痛觉过敏的 MRL/lpr 小鼠中，其表达显着增加。小胶质细胞中 GPR109A 受体的激活通过抑制白细胞介素 18 (IL-18) 的产生来减弱谷氨酸能突触活性。我们提供的证据表明，GPR109A 的激活通过抑制 p38 MAPK 活性和 IL-18 的产生来减轻 SLE 动物模型中的热痛觉过敏。我们的研究表明，靶向小胶质细胞 GPR109A 是逆转脊髓神经炎症、异常兴奋性突触活动和治疗 SLE 引起的热痛觉过敏的有效方法。
Many patients with systemic lupus erythematosus (SLE) live with chronic pain despite advances in medical management in reducing mortality related to SLE. Few animal studies have addressed mechanisms and treatment for chronic pain caused by SLE. In this study, we provide the first evidence for the analgesic effects of a GPR109A specific agonist (MK1903) and its action mechanisms in thermal hyperalgesia in female MRL/lpr mice, an SLE mouse model. Specifically, we show that MRL/lpr mice had a higher sensitivity to thermal stimuli at age 11–16 weeks, which was accompanied with significantly microglial and astrocytic activation, increases in p38 MAPK and glutamatergic synaptic activities in the spinal dorsal horn. We demonstrate that thermal hyperalgesia in MRL/lpr mice was significantly attenuated by intrathecal injection of MK1903. GPR109A was expressed in spinal microglia but not astrocytes or neurons. Its expression was significantly increased in MRL/lpr mice with thermal hyperalgesia. Activation of GPR109A receptors in microglia attenuated glutamatergic synaptic activity via suppressing production of interleukin-18 (IL-18). We provide evidence that activation of GPR109A attenuated thermal hyperalgesia in the SLE animal model via suppressing p38 MAPK activity and production of IL-18. Our study suggests that targeting the microglial GPR109A is a potent approach for reversing spinal neuroinflammation, abnormal excitatory synaptic activity, and management of thermal hyperalgesia caused by SLE.
登录
查看更多内容
小胶质细胞和白介素 18 参与强直性坐骨神经刺激引起的脊髓伤害性反应的长期增强
影响因子：
5.6
作者：
Chu, Yu-Xia;Zhang, Yu-Qiu;Zhao, Zhi-Qi
通讯作者：
Zhao, Zhi-Qi
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
5.8
作者：
Knowles, HJ;Poole, RT;Harris, AL
通讯作者：
Harris, AL
影响因子：
27.4
作者：
EDWARDS, JCW;COOKE, A;WILLOUGHBY, DA
通讯作者：
WILLOUGHBY, DA
影响因子：
--
作者：
Cox, Jennifer H.;Starr, Amanda E.;Overall, Christopher M.
通讯作者：
Overall, Christopher M.