Heme oxygenase-1 promotes neuron survival through down-regulation of neuronal NLRP1 expression after spinal cord injury.
Heme oxygenase-1 promotes neuron survival through down-regulation of neuronal NLRP1 expression after spinal cord injury.
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DOI：
10.1186/s12974-016-0521-y
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发表时间：
2016-02-29
影响因子：
9.3
通讯作者：
Lin JH
中科院分区：
文献类型：
--
作者：
Lin WP;Xiong GP;Lin Q;Chen XW;Zhang LQ;Shi JX;Ke QF;Lin JH
了解脊髓损伤（SCI）中神经元死亡的机制，并开发SCI诱导损伤的新治疗方法对于功能恢复至关重要。在这里，我们研究了血红素氧合酶-1（HO-1）在SCI后神经保护中的作用。制备表达HO-1的腺相关病毒，并在建立脊髓损伤模型前将其注射到大鼠脊髓内。HO-1的表达，炎性小体激活，并通过定量聚合酶链反应，免疫组织化学染色，免疫印迹和免疫沉淀的炎性细胞因子的存在。末端脱氧核苷酸转移酶dUTP缺口末端标记法检测神经元凋亡。评估后肢运动功能的神经损伤程度。在体外模型中，使用过氧化氢在培养的原代脊髓神经元中诱导类似的炎性小体活化，然后在有或没有转导表达HO-1的腺相关病毒的情况下评估上述参数。脊髓损伤后内源性HO-1的表达与Nod样受体蛋白1（Nod-like receptor protein 1，NLRP 1）的表达及NLRP 1炎性小体的形成密切相关。给予表达HO-1的腺相关病毒有效地降低了NLRP 1的表达，因此减轻了NLRP 1炎性小体诱导的神经元死亡并改善了功能恢复。在体外模型中，外源性HO-1表达通过抑制NLRP 1表达保护神经元免受过氧化氢诱导的神经元死亡。此外，HO-1抑制转录激活因子4（ATF 4）的表达，其是调节NLRP 1表达的转录因子。HO-1通过抑制NLRP 1炎性小体形成保护脊髓损伤后神经元。本文的在线版本（doi：10.1186/s12974-016-0521-y）包含补充材料，可供授权用户使用。
Understanding the mechanisms underlying neuronal death in spinal cord injury (SCI) and developing novel therapeutic approaches for SCI-induced damage are critical for functional recovery. Here we investigated the role of heme oxygenase-1 (HO-1) in neuroprotection after SCI. Adeno-associated virus expressing HO-1 was prepared and injected into rat spinal cords before SCI model was performed. HO-1 expression, inflammasome activation, and the presence of inflammatory cytokines were determined by quantitative polymerase chain reaction, immunohistological staining, immunoblot, and immunoprecipitation. Neuronal apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling. The hindlimb locomotor function was evaluated for extent of neurologic damage. In an in vitro model, hydrogen peroxide was used to induce similar inflammasome activation in cultured primary spinal cord neurons, followed by evaluation of above parameters with or without transduction of HO-1-expressing adeno-associated virus. Endogenous HO-1 expression was found in spinal cord neurons after SCI in vivo, in association with the expression of Nod-like receptor protein 1 (NLRP1) and the formation of NLRP1 inflammasomes. Administration of HO-1-expressing adeno-associated virus effectively decreased expression of NLRP1, therefore alleviating NLRP1 inflammasome-induced neuronal death and improving functional recovery. In the in vitro model, exogenous HO-1 expression protected neurons from hydrogen peroxide-induced neuronal death by inhibiting NLRP1 expression. In addition, HO-1 inhibited expression of activating transcription factor 4 (ATF4), which is a transcription factor regulating NLRP1 expression. HO-1 protects spinal cord neurons after SCI through inhibiting NLRP1 inflammasome formation. The online version of this article (doi:10.1186/s12974-016-0521-y) contains supplementary material, which is available to authorized users.