Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice.
Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice.
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DOI：
10.1002/ana.24304
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发表时间：
2015-01
影响因子：
11.2
通讯作者：
Weiner, Howard L.
中科院分区：
文献类型：
--
作者：
Butovsky, Oleg;Jedrychowski, Mark P.;Cialic, Ron;Krasemann, Susanne;Murugaiyan, Gopal;Fanek, Zain;Greco, David J.;Wu, Pauline M.;Doykan, Camille E.;Kiner, Olga;Lawson, Robert J.;Frosch, Matthew P.;Pochet, Nathalie;El Fatimy, Rachid;Krichevsky, Anna M.;Gygi, Steven P.;Lassmann, Hans;Berry, James;Cudkowicz, Merit E.;Weiner, Howard L.
研究miR-155在SOD 1小鼠模型和人类散发性和家族性肌萎缩侧索硬化症（ALS）中的作用。在来自SOD 1小鼠的脊髓小胶质细胞、脾单核细胞和脊髓组织以及家族性和散发性ALS的脊髓组织中测量Nanostring microRNA、小胶质细胞和免疫基因谱、蛋白质质谱和RNA-seq分析。在SOD 1小鼠中，通过基因消融或通过外周或中心施用的抗miR-155抑制剂靶向miR-155。在SOD 1小鼠中，我们发现了表征小胶质细胞的分子特征的丢失和miR-155的表达增加。小胶质细胞分子P2 ry 12、Tmem 119、Olfml 3、转录因子Egr 1、Atf 3、Jun、Fos、Mafb以及对小胶质细胞生存至关重要的上游调节因子Csf 1 r、Tgfb 1和Tgfbr 1均出现缺失。小胶质细胞的生物学功能受到抑制，包括吞噬作用。miR-155的基因切除使SOD 1小鼠的存活率增加了51天（雌性）和27天（雄性），并恢复了异常的小胶质细胞和单核细胞分子特征。SOD 1男性的疾病严重程度与小胶质细胞中炎症基因（包括Apoe）的早期上调相关。用APOE处理成年小胶质细胞抑制了M0独特的小胶质细胞特征并诱导了M1样表型。miR-155在家族性和散发性ALS的脊髓中表达增加。我们在人类ALS脊髓中鉴定的失调蛋白在SOD 1G 93 A/miR-155−/−小鼠中恢复。脑室内抗miR-155治疗解除了小胶质细胞miR-155靶向基因的抑制，外周抗miR-155治疗延长了生存期。我们在SOD 1小鼠以及散发性和家族性人类ALS中发现了miR-155的过表达。在SOD 1小鼠中靶向miR-155可恢复功能失调的小胶质细胞并改善疾病。这些发现将miR-155确定为治疗ALS的治疗靶点。
To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS). Nanostring microRNA, microglia and immune gene profiles, protein mass spectrometry and RNA-seq analyses were measured in spinal cord microglia, splenic monocytes and spinal cord tissue from SOD1 mice and in spinal cord tissue of familial and sporadic ALS. miR-155 was targeted by genetic ablation or by peripheral or centrally administered anti-miR-155 inhibitor in SOD1 mice. In SOD1 mice we found loss of the molecular signature that characterizes microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, Mafb and the upstream regulators Csf1r, Tgfb1 and Tgfbr1 which are essential for microglial survival. Microglia biological functions were suppressed including phagocytosis. Genetic ablation of miR-155 increased survival in SOD1 mice by 51d in females and 27d in males and restored the abnormal microglia and monocyte molecular signatures. Disease severity in SOD1 males was associated with early upregulation of inflammatory genes including Apoe in microglia. Treatment of adult microglia with APOE suppressed the M0-unique microglia signature and induced a M1-like phenotype. miR-155 expression was increased in the spinal cord of both familial and sporadic ALS. Dysregulated proteins that we identified in human ALS spinal cord were restored in SOD1G93A/miR-155−/− mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes and peripheral anti-miR-155 treatment prolonged survival. We found overexpression of miR-155 in the SOD1 mouse and in both sporadic and familial human ALS. Targeting miR-155 in SOD1 mice restores dysfunctional microglia and ameliorates disease. These findings identify miR-155 as a therapeutic target for the treatment of ALS.
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影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
25
作者：
Kang, Shin H.;Li, Ying;Fukaya, Masahiro;Lorenzini, Ileana;Cleveland, Don W.;Ostrow, Lyle W.;Rothstein, Jeffrey D.;Bergles, Dwight E.
通讯作者：
Bergles, Dwight E.
影响因子：
11.2
作者：
Henkel, JS;Engelhardt, JI;Appel, SH
通讯作者：
Appel, SH
影响因子：
4.8
作者：
Bala, Shashi;Marcos, Miguel;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi
影响因子：
4.8
作者：
Botelho, Hugo M.;Leal, Sonia S.;Gomes, Claudio M.
通讯作者：
Gomes, Claudio M.