Combination of autophagy and NFE2L2/NRF2 activation as a treatment approach for neuropathic pain.
Combination of autophagy and NFE2L2/NRF2 activation as a treatment approach for neuropathic pain.
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自噬和 NFE2L2/NRF2 激活相结合作为神经病理性疼痛的治疗方法
DOI：
10.1080/15548627.2021.1900498
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发表时间：
2021-12
期刊：
影响因子：
13.3
通讯作者：
Yuan H
中科院分区：
文献类型：
--
作者：
Li J;Tian M;Hua T;Wang H;Yang M;Li W;Zhang X;Yuan H
巨噬/自噬是一个进化保守的过程，在免疫炎症和神经系统稳态的调节中起重要作用。然而，自噬在疼痛中的确切作用和机制尚不清楚。在这里，我们发现自噬通量受损主要发生在神经性疼痛维持期间的星形胶质细胞中。无论在神经性疼痛的诱导或维持阶段，自噬的激活都能减轻疼痛水平，而自噬的抑制则会加重疼痛水平。此外，自噬抑制或激活后，神经炎症和活性氧（ROS）水平升高或降低。进一步研究表明，抑制自噬减缓了诱导，但增加了神经炎症反应的维持，这可能通过促进TRAF6 （TNF受体相关因子6）与K63泛素化蛋白的结合，增加B细胞中p-MAPK8/JNK（丝裂原活化蛋白激酶8）和kappa轻多肽基因增强子核因子（NFKB/NF-κB）的水平来实现。由于星形胶质细胞释放的谷胱甘肽水平降低，自噬受损也降低了星形胶质细胞对神经元抗ROS应激的保护作用，而激活NFE2L2/NRF2 （nuclear factor, erythroid derived 2, like 2）通路可改善这种保护作用。我们还证明，与单独激活自噬相比，同时激活自噬和NFE2L2途径可以进一步缓解疼痛。我们的研究提供了自噬参与神经性疼痛调控的潜在机制，自噬和NFE2L2激活的结合可能是神经性疼痛的一种新的治疗方法。缩写：3-MA: 3-甲基腺嘌呤；8-OHdG: 8-hydroxydeoxy-guanosine;ACTB：肌动蛋白；α -氨基-3-羟基-5-甲基-4-异恶唑丙酸受体；ATG: autophagy-related;CAMK2/CaMKII：钙/钙调素依赖性蛋白激酶II；CCL7：趋化因子（C-C基序）配体；CGAS：环GMP-AMP合成酶；CQ:氯喹;GABA: gamma-aminobutyrate;GCLC：谷氨酸半胱氨酸连接酶，催化亚基；GFAP：胶质原纤维酸性蛋白；谷胱甘肽,谷胱甘肽;HMOX1/HO-1：血红素加氧酶1；KEAP1: kelch-like ECH-associated protein 1；MAP1LC3/LC3-II：微管相关蛋白1轻链3 β（磷脂酰乙醇胺缀合形式）；MAPK：丝裂原活化蛋白激酶；MAPK1/ERK：丝裂原活化蛋白激酶1；MMP2：基质金属肽酶2；MAPK8/JNK：丝裂原活化蛋白激酶8；MAPK14/p38：丝裂原活化蛋白激酶14；NFE2L2/NRF2：核因子，红系衍生2，类2；B细胞kappa轻多肽基因增强子核因子NF-κBROS：活性氧；SLC12A5：溶质载流子族12，成员5；SNL：脊神经结扎；TLR4: toll样受体4；TRAF6: TNF受体相关因子；TRP：瞬时受体电位。
Macroautophagy/autophagy, an evolutionarily conserved process, plays an important role in the regulation of immune inflammation and nervous system homeostasis. However, the exact role and mechanism of autophagy in pain is still unclear. Here, we showed that impaired autophagy flux mainly occurred in astrocytes during the maintenance of neuropathic pain. No matter the stage of neuropathic pain induction or maintenance, activation of autophagy relieved the level of pain, whereas inhibition of autophagy aggravated pain. Moreover, the levels of neuroinflammation and reactive oxygen species (ROS) were increased or decreased following autophagy inhibition or activation. Further study showed that inhibition of autophagy slowed the induction, but increased the maintenance of neuroinflammatory responses, which could be achieved by promoting the binding of TRAF6 (TNF receptor-associated factor 6) to K63 ubiquitinated protein, and increasing the levels of p-MAPK8/JNK (mitogen-activated protein kinase 8) and nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB/NF-κB). Impaired autophagy also reduced the protective effect of astrocytes on neurons against ROS stress because of the decrease in the level of glutathione released by astrocytes, which could be improved by activating the NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) pathway. We also demonstrated that simultaneous activation of autophagy and the NFE2L2 pathway further relieved pain, compared to activating autophagy alone. Our study provides an underlying mechanism by which autophagy participates in the regulation of neuropathic pain, and a combination of autophagy and NFE2L2 activation may be a new treatment approach for neuropathic pain. Abbreviation: 3-MA: 3-methyladenine; 8-OHdG: 8-hydroxydeoxy-guanosine; ACTB: actin, beta; AMPAR: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor; ATG: autophagy-related; CAMK2/CaMKII: calcium/calmodulin-dependent protein kinase II; CCL7: chemokine (C-C motif) ligand 7; CGAS: cyclic GMP-AMP synthase; CQ: chloroquine; GABA: gamma-aminobutyrate; GCLC: glutamate-cysteine ligase, catalytic subunit; GFAP: glial fibrillary acidic protein; GSH: glutathione; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch-like ECH-associated protein 1; MAP1LC3/LC3-II: microtubule-associated protein 1 light chain 3 beta (phosphatidylethanolamine-conjugated form); MAPK: mitogen-activated protein kinase; MAPK1/ERK: mitogen-activated protein kinase 1; MMP2: matrix metallopeptidase 2; MAPK8/JNK: mitogen-activated protein kinase 8; MAPK14/p38: mitogen-activated protein kinase 14; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; ROS: reactive oxygen species; SLC12A5: solute carrier family 12, member 5; SNL: spinal nerve ligation; TLR4: toll-like receptor 4; TRAF6: TNF receptor-associated factor; TRP: transient receptor potential.
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