Transcription factor MafB contributes to the activation of spinal microglia underlying neuropathic pain development
Transcription factor MafB contributes to the activation of spinal microglia underlying neuropathic pain development
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DOI：
10.1002/glia.23570
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发表时间：
2019-04-01
期刊：
影响因子：
6.2
通讯作者：
Tsuda, Makoto
中科院分区：
文献类型：
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作者：
Tozaki-Saitoh, Hidetoshi;Masuda, Junya;Tsuda, Makoto
小胶质细胞是中枢神经系统的病理效应器和放大器，经历多种形式的激活。周围神经损伤后脊髓小胶质细胞激活（PNI）是一种被充分研究的小胶质细胞诱导的病理模式，是神经性疼痛发展的关键事件，但促进小胶质细胞激活的转录因子尚不清楚。在这里，我们证明了mab，成熟小胶质细胞的主要转录调节因子，参与了小鼠神经性疼痛模型的病理。PNI选择性地引起脊髓小胶质细胞中mab表达的快速和显著增加，而在神经元中则没有。我们还发现脊髓中靶向MafB表达的microRNA mir-152在PNI后降低，鞘内给予mir-152模拟物抑制神经性疼痛的发展。使用杂合子mab缺陷小鼠和鞘内给药siRNA降低mab表达可减轻pni诱导的机械超敏反应的发展。此外，我们发现鞘内转移缺乏mab的小胶质细胞不会引起机械性超敏反应，条件mab敲除小鼠在PNI后不会发生神经性疼痛。我们认为mab是pni诱导的脊髓小胶质细胞表型改变和神经性疼痛发展的关键介质。
Microglia, which are pathological effectors and amplifiers in the central nervous system, undergo various forms of activation. A well-studied microglial-induced pathological paradigm, spinal microglial activation following peripheral nerve injury (PNI), is a key event for the development of neuropathic pain but the transcription factors contributing to microglial activation are less understood. Herein, we demonstrate that MafB, a dominant transcriptional regulator of mature microglia, is involved in the pathology of a mouse model of neuropathic pain. PNI caused a rapid and marked increase of MafB expression selectively in spinal microglia but not in neurons. We also found that the microRNA mir-152 in the spinal cord which targets MafB expression decreased after PNI, and intrathecal administration of mir-152 mimic suppressed the development of neuropathic pain. Reduced MafB expression using heterozygous Mafb deficient mice and by intrathecal administration of siRNA alleviated the development of PNI-induced mechanical hypersensitivity. Furthermore, we found that intrathecal transfer of Mafb deficient microglia did not induce mechanical hypersensitivity and that conditional Mafb knockout mice did not develop neuropathic pain after PNI. We propose that MafB is a key mediator of the PNI-induced phenotypic alteration of spinal microglia and neuropathic pain development.