Mas-related G protein-coupled receptor D participates in inflammatory pain by promoting NF-κB activation through interaction with TAK1 and IKK complex
Mas-related G protein-coupled receptor D participates in inflammatory pain by promoting NF-κB activation through interaction with TAK1 and IKK complex
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Mas相关G蛋白偶联受体D通过与TAK1和IKK复合物相互作用促进NF-κB激活来参与炎症疼痛
DOI：
10.1016/j.cellsig.2020.109813
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发表时间：
2020-12-01
影响因子：
4.8
通讯作者：
Wan, Fengyi
中科院分区：
文献类型：
--
作者：
Lan, Lei;Xu, Miao;Wan, Fengyi
MAS相关G蛋白偶联受体D（MrgprD）主要表达于背根神经节（DRG）的小直径感觉神经元。以往的研究结果表明，MrgprD参与机械性痛觉过敏和神经损伤引起的神经病理性疼痛。然而，MrgprD是否以及如何参与炎性疼痛仍然是难以捉摸的。在这里，我们使用的小鼠模型，慢性炎症性疼痛建立腹腔注射脂多糖（LPS）。LPS注射可引起小鼠明显的外周神经炎症和机械性痛觉过敏，并可增加DRG中MrgprD的表达。LPS给药还增加了腰椎4 DRG中MrgprD表达神经元的比例。在行为上，LPS诱导的超敏反应，机械和冷刺激，但不是热刺激，在Mrgprd基因敲除小鼠与野生型同窝仔相比，大大减弱。DRGs中的Mrgprd缺失抑制LPS触发的NF-κ B信号通路的激活，并减弱LPS诱导的促炎因子的上调。此外，在稳定表达小鼠toll样受体4（TLR 4）的HEK 293细胞中异位过表达MrgprD显著促进LPS诱导的NF-κ B活化，并增强NF-κ B的DNA结合活性。此外，MrgprD与TGF-β激活的激酶1（TAK 1）和I-κ-B-激酶（IKK）复合物发生物理相互作用，但不与小鼠DRG中的丝裂原激活蛋白激酶（MAPK）发生物理相互作用。在巨噬细胞样RAW 264.7细胞中，MrgprD还与TAK 1和IKK复合物相互作用，MrgprD激动剂处理引起NF-κ B信号通路的激活，但不引起丝裂原活化蛋白激酶（MAPK）信号通路的激活。我们的研究结果表明，MrgprD通过促进典型的NF-κ B B活化促进LPS触发的持续性炎性痛觉过敏的发展，突出了MrgprD在NF-κ B介导的炎症和慢性疼痛中的重要作用。
Mas-related G protein-coupled receptor D (MrgprD) is mainly expressed in small-diameter sensory neurons of the dorsal root ganglion (DRG). Results from previous studies suggest that MrgprD participates in mechanical hyperalgesia and nerve injury-induced neuropathic pain. However, it remains elusive whether and how MrgprD is involved in inflammatory pain. Here, we used a mouse model of chronic inflammatory pain established by intraperitoneal administration of lipopolysaccharide (LPS). The LPS injection induced an evident peripheral neuroinflammation and mechanical hyperalgesia in the mice and increased MrgprD expression in the DRG. The LPS administration also augmented the proportion of MrgprD-expressing neurons in the lumbar 4 DRG. Behaviorally, the LPS-induced hypersensitivities to mechanical and cold stimuli, but not to a heat stimulus, were substantially attenuated in Mrgprd-knockout mice compared with wildtype littermates. Mrgprd deletion in DRGs suppressed the LPS-triggered activation of the NF-kappa B signaling pathway and attenuated LPS-induced up-regulation of pro-inflammatory factors. Moreover, ectopic overexpression of MrgprD in HEK293 cells stably expressing mouse toll-like receptor 4 (TLR4) markedly promoted the LPS-induced NF-kappa B activation and enhanced NF-kappa B's DNA-binding activity. Furthermore, MrgprD physically interacted with TGF-beta-activated kinase 1 (TAK1) and I-kappa-B-kinase (IKK) complexes, but not with mitogen-activated protein kinases (MAPKs) in mouse DRGs. In macrophage-like RAW 264.7 cells, MrgprD also interacted with TAK1 and IKK complex, and the treatment of MrgprD agonist elicited the activation of NF-kappa B signaling, but not of mitogen-activated protein kinases (MAPKs) signaling pathway. Our findings indicate that MrgprD facilitates the development of LPS-triggered persistent inflammatory hyperalgesia by promoting canonical NF-kappa B activation, highlighting the important roles of MrgprD in NF-kappa B-mediated inflammation and chronic pain.