NLRP3-Mediated Piezo1 Upregulation in ACC Inhibitory Parvalbumin-Expressing Interneurons Is Involved in Pain Processing after Peripheral Nerve Injury.
NLRP3-Mediated Piezo1 Upregulation in ACC Inhibitory Parvalbumin-Expressing Interneurons Is Involved in Pain Processing after Peripheral Nerve Injury.
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NLRP3 介导的 ACC 抑制性小白蛋白表达中间神经元中的 Piezo1 上调参与周围神经损伤后的疼痛处理
DOI：
10.3390/ijms232113035
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发表时间：
2022-10-27
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
前扣带皮层（ACC）对疼痛信息处理尤为关键。周围神经损伤会引发ACC神经元的过度兴奋，并介导对脊髓背角的下行易化作用。机械门控离子通道Piezo1参与周围神经系统中疼痛信息的传递。然而，Piezo1在大脑疼痛处理中的作用尚不清楚。在本研究中，我们发现坐骨神经分支选择性损伤（SNI）会使双侧ACC中表达小白蛋白（PV）的抑制性中间神经元（PV-INs）中Piezo1蛋白水平升高，而在表达谷氨酰胺能的CaMKⅡ⁺神经元中则不会。在SNI慢性疼痛模型中，观察到PV-INs数量减少，而CaMKⅡ⁺神经元数量未减少，且抑制性突触终末显著减少。此外，对ACC中小胶质细胞形态变化的观察显示，它们发生了激活的阿米巴样转变，突起长度缩短，胞体面积增大。结合Iba1⁺小胶质细胞对Piezo1阳性神经元的包裹现象，SNI后PV-INs的缺失可能是小胶质细胞吞噬作用导致的。在细胞实验中，向BV2细胞培养物或ACC神经元原代培养物中添加重组大鼠肿瘤坏死因子-α（rrTNF），会提高Piezo1和含NOD样受体（NLR）家族吡啶结构域3（NLRP3）的蛋白水平。在这些细胞中给予NLRP3抑制剂MCC950，在体外可阻断rrTNF诱导的半胱天冬酶-1和白细胞介素-1β（激活的NLRP3炎性小体的关键下游因子）的表达，在体内可逆转SNI诱导的ACC中Piezo1的过表达，并减轻SNI诱导的痛觉过敏。这些结果表明，NLRP3可能是导致SNI中Piezo1上调的关键因素，通过诱导小胶质细胞对PV-INs的吞噬作用，促使ACC兴奋与抑制失衡，从而促进脊髓疼痛传递。
The anterior cingulate cortex (ACC) is particularly critical for pain information processing. Peripheral nerve injury triggers neuronal hyper-excitability in the ACC and mediates descending facilitation to the spinal dorsal horn. The mechanically gated ion channel Piezo1 is involved in the transmission of pain information in the peripheral nervous system. However, the pain-processing role of Piezo1 in the brain is unknown. In this work, we found that spared (sciatic) nerve injury (SNI) increased Piezo1 protein levels in inhibitory parvalbumin (PV)-expressing interneurons (PV-INs) but not in glutaminergic CaMKⅡ+ neurons, in the bilateral ACC. A reduction in the number of PV-INs but not in the number of CaMKⅡ+ neurons and a significant reduction in inhibitory synaptic terminals was observed in the SNI chronic pain model. Further, observation of morphological changes in the microglia in the ACC showed their activated amoeba-like transformation, with a reduction in process length and an increase in cell body area. Combined with the encapsulation of Piezo1-positive neurons by Iba1+ microglia, the loss of PV-INs after SNI might result from phagocytosis by the microglia. In cellular experiments, administration of recombinant rat TNF-α (rrTNF) to the BV2 cell culture or ACC neuron primary culture elevated the protein levels of Piezo1 and NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3). The administration of the NLRP3 inhibitor MCC950 in these cells blocked the rrTNF-induced expression of caspase-1 and interleukin-1β (key downstream factors of the activated NLRP3 inflammasome) in vitro and reversed the SNI-induced Piezo1 overexpression in the ACC and alleviated SNI-induced allodynia in vivo. These results suggest that NLRP3 may be the key factor in causing Piezo1 upregulation in SNI, promoting an imbalance between ACC excitation and inhibition by inducing the microglial phagocytosis of PV-INs and, thereby, facilitating spinal pain transmission.
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