Extracellular and nuclear roles of IL-37 after spinal cord injury.
Extracellular and nuclear roles of IL-37 after spinal cord injury.
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DOI：
10.1016/j.bbi.2020.09.026
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Lopez-Vales R
中科院分区：
文献类型：
--
作者：
Amo-Aparicio J;Sanchez-Fernandez A;Li S;Eisenmesser EZ;Garlanda C;Dinarello CA;Lopez-Vales R
白细胞介素37 （IL-37）是白细胞介素1家族的一种抗炎细胞因子。表达人il -37基因（hIL-37Tg）的转基因小鼠在几种动物疾病模型中显示出保护作用。我们小组先前的数据显示，IL-37限制脊髓损伤（SCI）后的炎症，改善组织损伤和功能缺陷。IL-37可通过转运至细胞核或作为细胞外细胞因子发挥其抗炎作用。然而，脊髓损伤后的这种保护是通过转运到细胞核，激活细胞外受体，还是两者兼而有之，目前尚不清楚。在本研究中，我们使用不同的转基因动物来回答这个问题。我们证明，在缺乏细胞外受体IL-1R8的情况下，IL-37对脊髓损伤后功能和组织学结果的有益作用消失了，这表明IL-37作为细胞外细胞因子诱导了保护作用。另一方面，核功能被IL-37消除（il - 37d20atg）的转基因小鼠在脊髓损伤后的运动技能和髓磷脂保留方面均有显著改善，表明IL-37的保护作用不需要核途径。此外，我们还发现重组IL-37蛋白的治疗效果仅在细胞外受体IL-1R8存在的情况下产生，进一步强调了该细胞因子在脊髓损伤后细胞外功能的重要性。最后，我们发现重组IL-37蛋白在病变部位而不是全身给药时发挥治疗作用。这项工作首次证明了IL-37在脊髓损伤后的有益作用不需要易位到细胞核，并强调了IL-37的细胞外信号传导在介导神经保护作用中的重要性。
Interleukin 37 (IL-37) is an anti-inflammatory cytokine of the interleukin 1 family. Transgenic mice expressing the human form of the IL37 gene (hIL-37Tg) display protective effects in several animal models of disease. Previous data from our group revealed that IL-37 limits inflammation after spinal cord injury (SCI) and ameliorates tissue damage and functional deficits. IL-37 can exert its anti-inflammatory effects by translocating to the nucleus or acting as an extracellular cytokine. However, whether this protection after SCI is mediated by translocating to the nucleus, activating of extracellular receptors, or both, is currently unknown. In the present study, we used different transgenic animals to answer this question. We demonstrated that the beneficial effects of IL-37 on functional and histological outcomes after SCI were lost in the lack of the extracellular receptor IL-1R8, indicating that IL-37 induces protection as an extracellular cytokine. On the other hand, transgenic mice with the nuclear function of IL-37 abolished (hIL-37D20ATg) showed significant improvement in locomotor skills and myelin sparing after SCI, indicating that nuclear pathway is not required for the protective actions of IL-37. Moreover, we also showed that the therapeutic effects of the recombinant IL-37 protein are produced only in the presence of the extracellular receptor IL-1R8, further highlighting the importance of the extracellular function of this cytokine after SCI. Finally, we revealed that the administration of recombinant IL-37 protein exerted therapeutic actions when administered in the lesion site but not systemically. This work demonstrated for the first time that translocation of IL-37 to the nucleus is not required for the beneficial actions of this cytokine after SCI and highlights the importance of the extracellular signaling of IL-37 to mediate neuroprotective actions.
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影响因子：
16.6
作者：
Ballak, Dov B.;van Diepen, Janna A.;Stienstra, Rinke
通讯作者：
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影响因子：
32.4
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
--
作者：
Amo-Aparicio, Jesus;Martinez-Muriana, Anna;Lopez-Vales, Ruben
通讯作者：
Lopez-Vales, Ruben