Microglia shield the murine brain from damage mediated by the cytokines IL-6 and IFN-α.
PLX5622
calcification
central nervous system
depletion
interferon-alpha (IFN-α)
interleukin-6 (IL-6)
microglia
neuroinflammation
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2022
2022
Historique:
received:
05
09
2022
accepted:
13
10
2022
entrez:
17
11
2022
pubmed:
18
11
2022
medline:
22
11
2022
Statut:
epublish
Résumé
Sustained production of elevated levels of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is detrimental and directly contributes to the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Using transgenic mice with CNS-targeted production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN), we have recently demonstrated that microglia are prominent target and effector cells and mount stimulus-specific responses to these cytokines. In order to further clarify the phenotype and function of these cells, we treated GFAP-IL6 and GFAP-IFN mice with the CSF1R inhibitor PLX5622 to deplete microglia. We examined their ability to recover from acute microglia depletion, as well as the impact of chronic microglia depletion on the progression of disease. Following acute depletion in the brains of GFAP-IL6 mice, microglia repopulation was enhanced, while in GFAP-IFN mice, microglia did not repopulate the brain. Furthermore, chronic CSF1R inhibition was detrimental to the brain of GFAP-IL6 and GFAP-IFN mice and gave rise to severe CNS calcification which strongly correlated with the absence of microglia. In addition, PLX5622-treated GFAP-IFN mice had markedly reduced survival. Our findings provide evidence for novel microglia functions to protect against IFN-α-mediated neurotoxicity and neuronal dysregulation, as well as restrain calcification as a result of both IL-6- and IFN-α-induced neuroinflammation. Taken together, we demonstrate that CSF1R inhibition may be an undesirable target for therapeutic treatment of neuroinflammatory diseases that are driven by elevated IL-6 and IFN-α production.
Identifiants
pubmed: 36389783
doi: 10.3389/fimmu.2022.1036799
pmc: PMC9650248
doi:
Substances chimiques
Interleukin-6
0
Cytokines
0
PLX5622
0
Interferon-alpha
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1036799Informations de copyright
Copyright © 2022 West, Viengkhou, Campbell and Hofer.
Déclaration de conflit d'intérêts
Authors MH and IC received funding from Ionis Pharmaceuticals for experiments in an unrelated study using the GFAP-IFN mice. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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