Matsuda Kenichi, Kato Yugo, Okawara Yusuke, Sakamoto Makoto, Horikoshi Yosuke, Nakamura Kazuomi, Nakayama Yuji, Sato Hideyo, Homma Masato, Ueda Takahiro, Nakaso Kazuhiro
Division of Emergency and Disaster Medicine, Department of Surgery, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
Division of Biochemistry, Department of Pathophysiological and Therapeutic Sciences, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
Yonago Acta Med. 2025 Jul 28;68(3):227-236. doi: 10.33160/yam.2025.08.011. eCollection 2025 Aug.
Brain injury accompanied by hemorrhage, such as cerebral contusion or intracerebral hemorrhage, leads to the accumulation of activated microglia around the lesion. In addition, microglia at the site of injury can act either damagingly or protectively, depending on the time; for instance, it is damaging in the acute phase and protective in the chronic phase. Moreover, during brain injury, glutamate-induced excitotoxicity leads to secondary damage to neurons. However, the source of glutamate released from cells remains largely unknown. Our previous studies have revealed that cystine/glutamate antiporter system x (xc-) in microglia is an important source of glutamate release and that the induction of expression of xCT, a component molecule of xc-, is vital.
We investigated the effect of microglial xCT on traumatic brain injury using xCT-deficient mice.
In cultured microglia supplemented with crude brain extract and the affected side of the brain injury model accompanied by hemorrhage, the expression level of xCT was increased on the affected side, and induction was observed mainly in microglia. In addition, EAAT2 levels on the affected side decreased. On the affected side, the number of CD80-positive microglia was significantly increased, and the xCT expression rate was elevated in CD80-positive cells. Assuming that xCT in microglia is important, we investigated xCT-deficient mice and microglia-specific xCT knockdown mice and found that the extent of brain damage was milder than in wildtype mice. The proportion of CD80-positive microglia was lower than that in wild-type mice. Assuming that microglial xCT could be a therapeutic target, we performed an experiment using the xCT inhibitor SSZ administered intraperitoneally. The extent of damage was narrowed, and the ratio of CD80-positive microglia was reduced, demonstrating a therapeutic effect.
Thus, microglial xCT is important in the pathology of brain injury accompanied by bleeding and is considered a promising therapeutic target.
伴有出血的脑损伤，如脑挫裂伤或脑内出血，会导致损伤灶周围活化小胶质细胞的聚集。此外，损伤部位的小胶质细胞根据时间不同，其作用可能具有损伤性或保护性；例如，在急性期具有损伤性，在慢性期具有保护性。而且，在脑损伤期间，谷氨酸诱导的兴奋性毒性会导致神经元的继发性损伤。然而，细胞释放谷氨酸的来源在很大程度上仍不清楚。我们之前的研究表明，小胶质细胞中的胱氨酸/谷氨酸反向转运体系统x（xc-）是谷氨酸释放的重要来源，并且xc-的组成分子xCT的表达诱导至关重要。
我们使用xCT缺陷小鼠研究小胶质细胞xCT对创伤性脑损伤的影响。
在补充了粗脑提取物的培养小胶质细胞以及伴有出血的脑损伤模型的损伤侧，损伤侧xCT的表达水平升高，且主要在小胶质细胞中观察到诱导现象。此外，损伤侧的EAAT2水平降低。在损伤侧，CD80阳性小胶质细胞的数量显著增加，且CD80阳性细胞中的xCT表达率升高。假设小胶质细胞中的xCT很重要，我们研究了xCT缺陷小鼠和小胶质细胞特异性xCT敲低小鼠，发现脑损伤程度比野生型小鼠轻。CD80阳性小胶质细胞的比例低于野生型小鼠。假设小胶质细胞xCT可能是一个治疗靶点，我们进行了一项使用腹腔注射xCT抑制剂SSZ的实验。损伤程度缩小，CD80阳性小胶质细胞的比例降低，证明了治疗效果。
因此，小胶质细胞xCT在伴有出血的脑损伤病理学中很重要，被认为是一个有前景的治疗靶点。
