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

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Title: Absence of miRNA-146a Differentially Alters Microglia Function and Proteome
Authors: Martin, NA
Hyrlov, KH
Elkjaer, ML
Thygesen, EK
Wlodarczyk, A
Elbaek, KJ
Aboo, C
Okarmus, J
Benedikz, E
Reynolds, R
Hegedus, Z
Stensballe, A
Svenningsen, ÅF
Owens, T
Illes, Z
Item Type: Journal Article
Abstract: Background: MiR-146a is an important regulator of innate inflammatory responses and is also implicated in cell death and survival. Methods: 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). Results: When stimulated with LPS or myelin in vitro, microglia from KO mice expressed higher levels of IL-1β, TNF, IL-6, IL-10, CCL3, and CCL2 compared to WT. Stimulation increased migration and phagocytosis of WT but not KO microglia. CD11c+ microglia were induced by cuprizone (CPZ) in the WT mice but less in the KO. The proteome of ex vivo microglia was not different in miR-146a KO compared to WT mice, but CPZ treatment induced differential and reduced protein responses in the KO: GOT1, COX5b, CRYL1, and cystatin-C were specifically changed in KO microglia. We explored discriminative features of microglia proteomes: sparse Partial Least Squares-Discriminant Analysis showed the best discrimination when control and CPZ-treated conditions were compared. Cluster of ten proteins separated WT and miR-146a KO microglia after CPZ: among them were sensomes allowing to perceive the environment, Atp1a3 that belongs to the signature of CD11c+ microglia, and proteins related to inflammatory responses (S100A9, Ppm1g). Finally, we examined the expression of miR-146a and its validated target genes in different brain lesions of MS patients. MiR-146 was upregulated in all lesion types, and the highest expression was in active lesions. Nineteen of 88 validated target genes were significantly changed in active lesions, while none were changed in NAWM. Conclusion: Our data indicated that microglia is the major source of miR-146a in the CNS. The absence of miR-146a differentially affected microglia function and proteome, and miR-146a may play an important role in gene regulation of active MS lesions.
Issue Date: 5-Jun-2020
Date of Acceptance: 7-May-2020
URI: http://hdl.handle.net/10044/1/80354
DOI: 10.3389/fimmu.2020.01110
ISSN: 1664-3224
Publisher: Frontiers Media
Journal / Book Title: Frontiers in Immunology
Volume: 11
Copyright Statement: © 2020 Martin, Hyrlov, Elkjaer, Thygesen, Wlodarczyk, Elbaek, Aboo,Okarmus, Benedikz, Reynolds, Hegedus, Stensballe, Svenningsen, Owens and Illes.This is an open-access article distributed under the terms of the Creative CommonsAttribution License (CC BY). The use, distribution or reproduction in other forumsis permitted, provided the original author(s) and the copyright owner(s) are creditedand that the original publication in this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduction ispermitted which does notcomply with these terms.
Sponsor/Funder: Multiple Sclerosis Society
Medical Research Council (MRC)
Funder's Grant Number: 007/14
PO: FMIDY1596267
Keywords: CD11c
cuprizone
miR-146a
microglia
migration
multiple sclerosis lesion
phagocytosis
proteome
CD11c
cuprizone
miR-146a
microglia
migration
multiple sclerosis lesion
phagocytosis
proteome
1107 Immunology
1108 Medical Microbiology
Publication Status: Published
Conference Place: Switzerland
Article Number: ARTN 1110
Appears in Collections:Department of Brain Sciences