Herrmann Julia E, Imura Tetsuya, Song Bingbing, Qi Jingwei, Ao Yan, Nguyen Thu K, Korsak Rose A, Takeda Kiyoshi, Akira Shizuo, Sofroniew Michael V
Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095-1763, USA.
J Neurosci. 2008 Jul 9;28(28):7231-43. doi: 10.1523/JNEUROSCI.1709-08.2008.
Signaling mechanisms that regulate astrocyte reactivity and scar formation after spinal cord injury (SCI) are not well defined. We used the Cre recombinase (Cre)-loxP system under regulation of the mouse glial fibrillary acidic protein (GFAP) promoter to conditionally delete the cytokine and growth factor signal transducer, signal transducer and activator of transcription 3 (STAT3), from astrocytes. After SCI in GFAP-Cre reporter mice, >99% of spinal cord cells that exhibited Cre activity as detected by reporter protein expression were GFAP-expressing astrocytes. Conditional deletion (or knock-out) of STAT3 (STAT3-CKO) from astrocytes in GFAP-Cre-loxP mice was confirmed in vivo and in vitro. In uninjured adult STAT3-CKO mice, astrocytes appeared morphologically similar to those in STAT3+/+ mice except for a partially reduced expression of GFAP. In STAT3+/+ mice, phosphorylated STAT3 (pSTAT3) was not detectable in astrocytes in uninjured spinal cord, and pSTAT3 was markedly upregulated after SCI in astrocytes and other cell types near the injury. Mice with STAT3-CKO from astrocytes exhibited attenuated upregulation of GFAP, failure of astrocyte hypertrophy, and pronounced disruption of astroglial scar formation after SCI. These changes were associated with increased spread of inflammation, increased lesion volume and partially attenuated motor recovery over the first 28 d after SCI. These findings indicate that STAT3 signaling is a critical regulator of certain aspects of reactive astrogliosis and provide additional evidence that scar-forming astrocytes restrict the spread of inflammatory cells after SCI.
脊髓损伤（SCI）后调节星形胶质细胞反应性和瘢痕形成的信号机制尚未完全明确。我们利用在小鼠胶质纤维酸性蛋白（GFAP）启动子调控下的Cre重组酶（Cre）-loxP系统，有条件地从小胶质细胞中删除细胞因子和生长因子信号转导子、信号转导和转录激活因子3（STAT3）。在GFAP-Cre报告基因小鼠发生SCI后，通过报告蛋白表达检测到的表现出Cre活性的脊髓细胞中，>99%是表达GFAP的星形胶质细胞。在体内和体外均证实了GFAP-Cre-loxP小鼠星形胶质细胞中STAT3的条件性缺失（或敲除）（STAT3-CKO）。在未受伤的成年STAT3-CKO小鼠中，星形胶质细胞在形态上与STAT3+/+小鼠中的相似，只是GFAP的表达略有降低。在STAT3+/+小鼠中，未受伤脊髓的星形胶质细胞中检测不到磷酸化STAT3（pSTAT3），而在SCI后，损伤附近的星形胶质细胞和其他细胞类型中pSTAT3明显上调。星形胶质细胞中STAT3缺失的小鼠在SCI后表现出GFAP上调减弱、星形胶质细胞肥大失败以及星形胶质瘢痕形成明显破坏。这些变化与炎症扩散增加、损伤体积增大以及SCI后最初28天内运动恢复部分减弱有关。这些发现表明，STAT3信号是反应性星形胶质细胞增生某些方面的关键调节因子，并提供了额外的证据，即形成瘢痕的星形胶质细胞在SCI后限制了炎症细胞的扩散。
