Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia.
Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia.
复制标题
DOI：
10.1093/braincomms/fcab187
复制
发表时间：
2021
影响因子：
4.8
通讯作者：
Yen JH
中科院分区：
文献类型：
--
作者：
Kuo PC;Weng WT;Scofield BA;Furnas D;Paraiso HC;Yu IC;Yen JH
炎症刺激诱导免疫应答基因1的表达，其反过来通过将顺乌头酸从三羧酸循环中转移而催化衣康酸的产生。免疫应答基因1/衣康酸轴的免疫调节作用最近已在脂多糖激活的小鼠和人巨噬细胞中被证实。此外，衣康酸二甲酯，衣康酸衍生物，据报道，改善银屑病和多发性硬化症的动物模型中的疾病严重程度。目前，免疫应答基因1/衣康酸轴是否在缺血性卒中中发挥调节作用仍有待研究。在这项研究中，我们研究了免疫应答基因1是否在调节缺血性脑损伤中发挥作用。此外，免疫应答基因1在缺血性脑卒中中保护作用的分子机制也得到了阐明。我们的研究结果表明，免疫应答基因1在缺血性脑损伤后高度诱导。有趣的是，我们发现，与野生型中风对照组相比，IRG 1 −/−中风动物表现出加重的脑损伤，表现为脑梗死扩大。此外，IRG 1 −/−中风动物表现出加重的血脑屏障破坏，与缺血脑中伊文思蓝渗漏增加和免疫细胞浸润增加相关。此外，IRG 1 −/−中风动物显示出升高的小胶质细胞活化，表现为CD 68，CD 86和Iba 1表达增加。进一步的分析表明，免疫应答基因1诱导小胶质细胞缺血性中风后，免疫应答基因1的缺陷导致抑制小胶质细胞血红素氧合酶-1的表达，加重缺血性脑损伤。值得注意的是，给予衣康酸二甲酯以补偿免疫应答基因1/衣康酸轴的缺陷，导致小胶质细胞血红素加氧酶-1表达增强，减轻缺血性脑损伤，改善运动功能，降低IRG 1 −/−卒中动物的死亡率。总之，我们第一次证明了缺血性脑卒中后小胶质细胞免疫应答基因1的诱导作为一种内源性保护机制，通过血红素加氧酶-1的上调来抑制脑损伤。因此，我们的研究结果表明，靶向免疫应答基因1可能代表一种新的治疗缺血性中风的治疗方法。Kuo等报道，免疫应答基因1的诱导可能作为一种内源性保护机制来抑制缺血性卒中后的脑损伤。因此，他们的研究表明，靶向免疫应答基因1可能代表了治疗缺血性卒中的新治疗方法。
Inflammatory stimuli induce immunoresponsive gene 1 expression that in turn catalyses the production of itaconate through diverting cis-aconitate away from the tricarboxylic acid cycle. The immunoregulatory effect of the immunoresponsive gene 1/itaconate axis has been recently documented in lipopolysaccharide-activated mouse and human macrophages. In addition, dimethyl itaconate, an itaconate derivative, was reported to ameliorate disease severity in the animal models of psoriasis and multiple sclerosis. Currently, whether immunoresponsive gene 1/itaconate axis exerts a modulatory effect in ischaemic stroke remains unexplored. In this study, we investigated whether immunoresponsive gene 1 plays a role in modulating ischaemic brain injury. In addition, the molecular mechanism underlying the protective effects of immunoresponsive gene 1 in ischaemic stroke was elucidated. Our results showed that immunoresponsive gene 1 was highly induced in the ischaemic brain following ischaemic injury. Interestingly, we found that IRG1−/− stroke animals exhibited exacerbated brain injury, displayed with enlarged cerebral infarct, compared to wild-type stroke controls. Furthermore, IRG1−/− stroke animals presented aggravated blood–brain barrier disruption, associated with augmented Evans blue leakage and increased immune cell infiltrates in the ischaemic brain. Moreover, IRG1−/− stroke animals displayed elevated microglia activation, demonstrated with increased CD68, CD86 and Iba1 expression. Further analysis revealed that immunoresponsive gene 1 was induced in microglia after ischaemic stroke, and deficiency in immunoresponsive gene 1 resulted in repressed microglial heme oxygenase-1 expression and exacerbated ischaemic brain injury. Notably, the administration of dimethyl itaconate to compensate for the deficiency of immunoresponsive gene 1/itaconate axis led to enhanced microglial heme oxygenase-1 expression, alleviated ischaemic brain injury, improved motor function and decreased mortality in IRG1−/− stroke animals. In summary, we demonstrate for the first time that the induction of immunoresponsive gene 1 in microglia following ischaemic stroke serves as an endogenous protective mechanism to restrain brain injury through heme oxygenase-1 up-regulation. Thus, our findings suggest that targeting immunoresponsive gene 1 may represent a novel therapeutic approach for the treatment of ischaemic stroke. Kuo et al. reported that the induction of immunoresponsive gene 1 may serve as an endogenous protective mechanism to restrain brain injury following ischaemic stroke. Thus, their study suggests that targeting immunoresponsive gene 1 may represent a novel therapeutic approach for the treatment of ischaemic stroke.
登录
查看更多内容
影响因子：
3.3
作者：
Dotson, Abby L.;Wang, Jianming;Saugstad, Julie;Murphy, Stephanie J.;Offner, Halina
通讯作者：
Offner, Halina
Itaconate连接琥珀酸脱氢酶与巨噬细胞代谢重塑和调节炎症的联系。
影响因子：
29
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
通讯作者：
Artyomov MN
叔丁基氢醌通过激活小鼠局灶性脑缺血后核因子-E2相关因子2/血红素加氧酶-1增强血管生成和星形胶质细胞活化
影响因子：
3.1
作者：
Chen, Yanxia;Zhang, Xiangjian;He, Weiliang
通讯作者：
He, Weiliang
影响因子：
5.7
作者：
Lin, Cheng-Wei;Shen, Shing-Chun;Chen, Yen-Chou
通讯作者：
Chen, Yen-Chou
DOI：
10.4049/jimmunol.1601073
发表时间：
2017-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Hooper KM;Yen JH;Kong W;Rahbari KM;Kuo PC;Gamero AM;Ganea D
通讯作者：
Ganea D