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, Vol. 77, No. 1, 01.2015, p. 75-99.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -