Astrocytes play an indispensable role in maintaining a healthy, functional neural network in the central nervous system (CNS). A primary function of CNS astrocytes is to support the survival and function of neurons. In response to injury, astrocytes take on a reactive phenotype, which alters their molecular functions. Reactive astrocytes have been reported to be both beneficial and harmful to the CNS recovery process subsequent to injury. Understanding the molecular processes and regulatory proteins that determine the extent to which an astrocyte hinders or supports neuronal survival is important within the context of CNS repair. One protein that plays a role in modulating cellular survival is transglutaminase 2 (TG2). Global deletion of TG2 results in beneficial outcomes subsequent to in vivo ischemic brain injury. Ex vivo studies have also implicated TG2 as a negative regulator of astrocyte viability subsequent to injury. In this study we show that knocking down TG2 in astrocytes significantly increases their ability to protect neurons from oxygen glucose deprivation (OGD)/reperfusion injury. To begin to understand how deletion of TG2 in astrocytes improves their ability to protect neurons from injury, we performed transcriptome analysis of wild type and TG2^−/− astrocytes. TG2 deletion resulted in alterations in genes involved in extracellular matrix remodeling, cell adhesion and axon growth/guidance. In addition, the majority of genes that showed increases in the TG2^−/− astrocytes had predicted cJun/AP-1 binding motifs in their promoters. Furthermore, phospho-cJun levels were robustly elevated in TG2^−/− astrocytes, a finding which was consistent with the increase in expression of AP-1 responsive genes. These in vitro data were subsequently extended into an in vivo model to determine whether the absence of astrocytic TG2 improves outcomes after CNS injury. Our results show that, following a spinal cord injury, scar formation is significantly attenuated in mice with astrocyte-specific TG2 deletion compared to mice expressing normal TG2 levels. Taken together, these data indicate that TG2 plays a pivotal role in mediating reactive astrocyte properties following CNS injury. Further, the data suggest that limiting the AP-1 mediated pro-survival injury response may be a contributing factor to that the detrimental effects of astrocytic TG2.

星形胶质细胞在维持中枢神经系统（CNS）中健康，功能正常的神经网络中起着不可或缺的作用。中枢神经系统星形胶质细胞的主要功能是支持神经元的存活和功能。响应损伤，星形胶质细胞呈反应性表型，从而改变其分子功能。据报道，反应性星形胶质细胞对损伤后的CNS恢复过程既有益又有害。在中枢神经系统修复的背景下，了解决定星形胶质细胞阻碍或支持神经元存活的程度的分子过程和调节蛋白非常重要。在调节细胞存活中起作用的一种蛋白质是转谷氨酰胺酶2（TG2）。TG2的整体缺失可在体内产生有益的结果缺血性脑损伤。体外研究还表明，TG2在损伤后是星形胶质细胞生存能力的负调节剂。在这项研究中，我们表明，敲低星形胶质细胞中的TG2可以显着提高其保护神经元免受氧葡萄糖剥夺（OGD）/再灌注损伤的能力。为了开始了解星形胶质细胞中TG2的缺失如何提高其保护神经元免受损伤的能力，我们进行了野生型和TG2 ^-/-星形胶质细胞的转录组分析。TG2缺失导致参与细胞外基质重塑，细胞粘附和轴突生长/指导的基因改变。此外，大多数显示TG2 ^-/-升高的基因星状细胞在其启动子中已预测到cJun / AP-1结合基序。此外，在TG2 ^-/-星形胶质细胞中，磷酸化cJun水平显着升高，这一发现与AP-1反应基因表达的增加相一致。这些体外数据随后扩展到了体内该模型可确定缺少星形细胞TG2是否可改善CNS损伤后的结局。我们的结果表明，脊髓损伤后，与表达正常TG2水平的小鼠相比，星形胶质细胞特异性TG2缺失的小鼠瘢痕形成明显减弱。综上所述，这些数据表明TG2在CNS损伤后在介导反应性星形胶质细胞特性中起关键作用。此外，数据表明，限制AP-1介导的生存前损伤反应可能是导致星形胶质TG2有害的因素。