Inhibition of TRPV1 by SHP-1 in nociceptive primary sensory neurons is critical in PD-L1 analgesia.
Inhibition of TRPV1 by SHP-1 in nociceptive primary sensory neurons is critical in PD-L1 analgesia.
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DOI：
10.1172/jci.insight.137386
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发表时间：
2020-10-15
期刊：
影响因子：
8
通讯作者：
Zhang YQ
中科院分区：
文献类型：
--
作者：
Liu BL;Cao QL;Zhao X;Liu HZ;Zhang YQ
最近在背根神经节（DRG）神经元中发现程序性死亡配体1 （programmed death-ligand 1, PD-L1）受体PD-1， PD-L1通过调节神经元兴奋性激活PD-1抑制炎症和神经性疼痛。然而，PD-1在感觉神经元中的下游信号传导尚不清楚。本研究表明，PD-L1激活Src同源2结构域酪氨酸磷酸酶-1 (SHP-1)，下调DRG神经元中的瞬时受体电位香草酸样蛋白1 (TRPV1)，抑制小鼠骨癌疼痛。局部注射PD-L1产生镇痛作用。DRG神经元中的PD-1与TRPV1和SHP-1共定位。PD-L1诱导DRG TRPV1神经元SHP-1磷酸化，抑制TRPV1电流。小鼠中TRPV1的缺失可消除骨癌引起的热痛觉过敏和PD-L1镇痛。NaV1.8+神经元中SHP-1的条件性缺失加重了骨癌疼痛，减弱了PD-L1对TRPV1电流和疼痛的抑制作用。总之，我们的研究结果表明，PD-L1/PD-1信号通过抑制TRPV1活性来抑制骨癌疼痛。我们的研究结果还表明，感觉神经元中的SHP-1是一种内源性疼痛抑制剂，通过抑制TRPV1的功能来延缓骨癌疼痛的发展。在小鼠骨癌模型中，PD-L1/PD-1信号通过伤害性初级感觉神经元SHP-1的磷酸化抑制TRPV1活性并减轻疼痛样行为。
Recently programmed death-ligand 1 (PD-L1) receptor PD-1 was found in dorsal root ganglion (DRG) neurons, and PD-L1 activates PD-1 to inhibit inflammatory and neuropathic pain by modulating neuronal excitability. However, the downstream signaling of PD-1 in sensory neurons remains unclear. Here, we show that PD-L1 activated Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1) to downregulate transient receptor potential vanilloid 1 (TRPV1) in DRG neurons and inhibit bone cancer pain in mice. Local injection of PD-L1 produced analgesia. PD-1 in DRG neurons colocalized with TRPV1 and SHP-1. PD-L1 induced the phosphorylation of SHP-1 in DRG TRPV1 neurons and inhibited TRPV1 currents. Loss of TRPV1 in mice abolished bone cancer–induced thermal hyperalgesia and PD-L1 analgesia. Conditioned deletion of SHP-1 in NaV1.8+ neurons aggravated bone cancer pain and diminished the inhibition of PD-L1 on TRPV1 currents and pain. Together, our findings suggest that PD-L1/PD-1 signaling suppresses bone cancer pain via inhibition of TRPV1 activity. Our results also suggest that SHP-1 in sensory neurons is an endogenous pain inhibitor and delays the development of bone cancer pain via suppressing TRPV1 function. PD-L1/PD-1 signaling suppresses TRPV1 activity and alleviates pain-like behaviors via phosphorylation of SHP-1 in nociceptive primary sensory neurons in a mouse bone cancer model.