Dataset Information

Data in support of Absence of miRNA-146a differentially alters microglia function and proteome

ABSTRACT: MiR-146a is an important regulator of innate inflammatory responses and is also implicated in cell death and survival. Here, we identified microglia as the main cellular source of miR-146a among mouse CNS resident cells. We further characterized the phenotype of miR-146a KO microglia cells during in vivo demyelination induced by cuprizone (CPZ) and found reduced number of CD11c+ microglia in the KO compared to WT mice. Microglia were also isolated from the brain, and the proteome was analyzed by liquid chromatography mass spectrometry.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Microglial Cell

SUBMITTER: Allan Stensballe

LAB HEAD: Allan Stensballe

PROVIDER: PXD015939 | Pride | 2020-06-29

REPOSITORIES: Pride

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Publications

Absence of miRNA-146a Differentially Alters Microglia Function and Proteome.

Martin Nellie A NA Hyrlov Kirsten H KH Elkjaer Maria L ML Thygesen Eva K EK Wlodarczyk Agnieszka A Elbaek Kirstine J KJ Aboo Christopher C Okarmus Justyna J Benedikz Eirikur E Reynolds Richard R Hegedus Zoltan Z Stensballe Allan A Svenningsen Åsa Fex ÅF Owens Trevor T Illes Zsolt Z

Frontiers in immunology 20200605

<b>Background:</b> MiR-146a is an important regulator of innate inflammatory responses and is also implicated in cell death and survival. <b>Methods:</b> By sorting CNS resident cells, microglia were the main cellular source of miR-146a. Therefore, we investigated microglia function and phenotype in miR-146a knock-out (KO) mice, analyzed the proteome of KO and wild-type (WT) microglia by LC-MS/MS, and examined miR-146a expression in different brain lesions of patients with multiple sclerosis (MS ...[more]

PMID: 32582192

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Project description:Microglia is emerging as a key player in the progression of neurodegenerative diseases. In pediatric neurodegenerative diseases like mucopolysaccharidosis type III (MPSIII), the progressive accumulation of abnormal glycosaminoglycans (GAGs) induces a severe neuroinflammation by triggering a microglial production of pro-inflammatory cytokines and chemokines via TLR4-dependent pathway.We have already shown the essential role of microglia in the development of neuroinflammation but the extent of its contribution in the neuropathology of MPSIII still remains unclear. Microglia interacts with other cells in the CNS via several mechanisms, including extracellular vesicle (EV) release. Although EVs have been shown to be implicated in the pathogenesis of adult neurodegenerative diseases, no reports have addressed the proteins and small RNAs profile of EVs released by microglia in the context of MPS and the effect of these EVs on neuronal functions. Here, we isolated EVs sub-populations from conditioned media of the murine BV-2 microglial cell line treated with GAG purified from urines of MPSIII patients and from age-matched unaffected children. By label-free quantitative proteomic using LC-MS/MS, we showed that MPS III-EVs are enriched in proteins involved in the inflammatory response and more specifically in neuroinflammation. On the other hand, proteins involved in axonal guidance, myelination or synaptogenesis were less abundant in MPSIII-EVs. RNA sequencing analysis revealed that MPSIII-EVs are highly enriched in 4 miRNAs - miR-155-5p, miR-146a-5p, miR-221-3p and miR-100-5p, also involved in neuroinflammation and neurodevelopment pathways. Moreover, we showed by immunofluorescence on primary cortical neurons isolated from wild type pups that MPSIII microglia-EVs reduce neurites total area, impair dendritic arborization, with a higher number of immature dendritic spines and also cause an increase in soma swelling, thus inducing a phenotype close to that observed in MPSIII brain mice. Theses findings uncover that MPSIII microglia-EVs can deliver a specific molecular message to surrounding naive cells and thus propagate neuroinflammation and deprive neurons of neurodevelopmental molecules.This work is the first report on the content of EVs released by MPSIII microglia and reveals a disease-associated signature, providing a framework for future studies on biomarkers to evaluate efficiency of emerging therapies.

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	10a_M_CPZKO_1c.raw	Raw
	10b_M_CPZKO_1c.raw	Raw
	11a_M_CPZKO_2.raw	Raw
	11b_M_CPZKO_2.raw	Raw
	12a_M_CPZKO_3.raw	Raw