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Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice

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Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. / 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; Fatimy, Rachid El; Krichevsky, Anna M; Gygi, Steven P; Lassmann, Hans; Berry, James; Cudkowicz, Merit E; Weiner, Howard L.

in: ANN NEUROL, Jahrgang 77, Nr. 1, 01.2015, S. 75-99.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Butovsky, O, Jedrychowski, MP, Cialic, R, Krasemann, S, Murugaiyan, G, Fanek, Z, Greco, DJ, Wu, PM, Doykan, CE, Kiner, O, Lawson, RJ, Frosch, MP, Pochet, N, Fatimy, RE, Krichevsky, AM, Gygi, SP, Lassmann, H, Berry, J, Cudkowicz, ME & Weiner, HL 2015, 'Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice', ANN NEUROL, Jg. 77, Nr. 1, S. 75-99. https://doi.org/10.1002/ana.24304

APA

Butovsky, O., Jedrychowski, M. P., Cialic, R., Krasemann, S., Murugaiyan, G., Fanek, Z., Greco, D. J., Wu, P. M., Doykan, C. E., Kiner, O., Lawson, R. J., Frosch, M. P., Pochet, N., Fatimy, R. E., Krichevsky, A. M., Gygi, S. P., Lassmann, H., Berry, J., Cudkowicz, M. E., & Weiner, H. L. (2015). Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. ANN NEUROL, 77(1), 75-99. https://doi.org/10.1002/ana.24304

Vancouver

Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. ANN NEUROL. 2015 Jan;77(1):75-99. https://doi.org/10.1002/ana.24304

Bibtex

@article{d12d6a6ce273415982dc1da0c65e3c3b,
title = "Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice",
abstract = "OBJECTIVE: To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).METHODS: 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.RESULTS: In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, and 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 51 days in females and 27 days 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 apolipoprotein E suppressed the M0-homeostatic unique microglia signature and induced an 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 SOD1(G93A) /miR-155(-/-) mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes, and peripheral anti-miR-155 treatment prolonged survival.INTERPRETATION: 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.",
keywords = "Aged, Amyotrophic Lateral Sclerosis, Animals, Apolipoproteins E, Cells, Cultured, Disease Models, Animal, Female, Gene Expression Regulation, Hippocampus, Humans, Male, Mice, Mice, Transgenic, MicroRNAs, Microglia, Middle Aged, Monocytes, Neurons, Oligoribonucleotides, Antisense, Phagocytosis, Spinal Cord, Superoxide Dismutase, Transforming Growth Factor beta",
author = "Oleg Butovsky and Jedrychowski, {Mark P} and Ron Cialic and Susanne Krasemann and Gopal Murugaiyan and Zain Fanek and Greco, {David J} and Wu, {Pauline M} and Doykan, {Camille E} and Olga Kiner and Lawson, {Robert J} and Frosch, {Matthew P} and Nathalie Pochet and Fatimy, {Rachid El} and Krichevsky, {Anna M} and Gygi, {Steven P} and Hans Lassmann and James Berry and Cudkowicz, {Merit E} and Weiner, {Howard L}",
note = "{\textcopyright} 2014 American Neurological Association.",
year = "2015",
month = jan,
doi = "10.1002/ana.24304",
language = "English",
volume = "77",
pages = "75--99",
journal = "ANN NEUROL",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

RIS

TY - JOUR

T1 - Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice

AU - Butovsky, Oleg

AU - Jedrychowski, Mark P

AU - Cialic, Ron

AU - Krasemann, Susanne

AU - Murugaiyan, Gopal

AU - Fanek, Zain

AU - Greco, David J

AU - Wu, Pauline M

AU - Doykan, Camille E

AU - Kiner, Olga

AU - Lawson, Robert J

AU - Frosch, Matthew P

AU - Pochet, Nathalie

AU - Fatimy, Rachid El

AU - Krichevsky, Anna M

AU - Gygi, Steven P

AU - Lassmann, Hans

AU - Berry, James

AU - Cudkowicz, Merit E

AU - Weiner, Howard L

N1 - © 2014 American Neurological Association.

PY - 2015/1

Y1 - 2015/1

N2 - OBJECTIVE: To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).METHODS: 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.RESULTS: In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, and 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 51 days in females and 27 days 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 apolipoprotein E suppressed the M0-homeostatic unique microglia signature and induced an 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 SOD1(G93A) /miR-155(-/-) mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes, and peripheral anti-miR-155 treatment prolonged survival.INTERPRETATION: 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.

AB - OBJECTIVE: To investigate miR-155 in the SOD1 mouse model and human sporadic and familial amyotrophic lateral sclerosis (ALS).METHODS: 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.RESULTS: In SOD1 mice, we found loss of the molecular signature that characterizes homeostatic microglia and increased expression of miR-155. There was loss of the microglial molecules P2ry12, Tmem119, Olfml3, transcription factors Egr1, Atf3, Jun, Fos, and 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 51 days in females and 27 days 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 apolipoprotein E suppressed the M0-homeostatic unique microglia signature and induced an 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 SOD1(G93A) /miR-155(-/-) mice. Intraventricular anti-miR-155 treatment derepressed microglial miR-155 targeted genes, and peripheral anti-miR-155 treatment prolonged survival.INTERPRETATION: 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.

KW - Aged

KW - Amyotrophic Lateral Sclerosis

KW - Animals

KW - Apolipoproteins E

KW - Cells, Cultured

KW - Disease Models, Animal

KW - Female

KW - Gene Expression Regulation

KW - Hippocampus

KW - Humans

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - MicroRNAs

KW - Microglia

KW - Middle Aged

KW - Monocytes

KW - Neurons

KW - Oligoribonucleotides, Antisense

KW - Phagocytosis

KW - Spinal Cord

KW - Superoxide Dismutase

KW - Transforming Growth Factor beta

U2 - 10.1002/ana.24304

DO - 10.1002/ana.24304

M3 - SCORING: Journal article

C2 - 25381879

VL - 77

SP - 75

EP - 99

JO - ANN NEUROL

JF - ANN NEUROL

SN - 0364-5134

IS - 1

ER -