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Series GSE231833 Query DataSets for GSE231833
Status Public on May 11, 2023
Title Interferon-gamma ameliorates experimental autoimmune encephalomyelitis by inducing homeostatic adaptation of microglia
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Compelling evidence has shown that interferon (IFN)-γ has dual effects in multiple sclerosis and in its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic and beneficial function. However, the mechanisms whereby IFN-γ may promote neuroprotection in EAE and its effects on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, the impact of IFN-γ at the peak of EAE, its effects on CNS infiltrating myeloid cells (MC) and microglia (MG), and the underlying cellular and molecular mechanisms were investigated. IFN-γ administration resulted in disease amelioration and attenuation of neuroinflammation associated with significantly lower frequencies of CNS CD11b+ myeloid cells and less infiltration of inflammatory cells and demyelination. A significant reduction in activated MG and enhanced resting MG was determined by flow cytometry and immunohistrochemistry. Primary MC/MG cultures obtained from spinal cord of IFN-γ-treated EAE mice that were ex vivo re-stimulated with a low dose (1 ng/ml) of IFN-γ and neuroantigen promoted a significantly higher induction of CD4+ regulatory T (Treg) cells associated with increased transforming growth factor (TGF)-β secretion. Additionally, IFN-γ-treated primary MC/MG cultures produced significantly lower nitrite in response to LPS challenge than control MC/MG. IFN-γ-treated EAE mice had a significantly higher frequency of CX3CR1high MC/MG and expressed lower levels of program death ligand 1 (PD-L1) than PBS-treated mice. Most CX3CR1highPD-L1lowCD11b+Ly6G- cells expressed MG markers (Tmem119, Sall2, and P2ry12), indicating that they represented an enriched MG subset (CX3CR1highPD-L1low MG). Amelioration of clinical symptoms and induction of CX3CR1highPD-L1low MG by IFN-γ were dependent on STAT-1. RNA-seq analyses revealed that in vivo treatment with IFN-γ promoted the induction of homeostatic CX3CR1highPD-L1low MG, upregulating the expression of genes associated with tolerogenic and anti-inflammatory roles and down-regulating pro-inflammatory genes. These analyses highlight the master role that IFN-γ plays in regulating microglial activity and provide new insights into the cellular and molecular mechanisms involved in the therapeutic activity of IFN-γ in EAE.
 
Overall design CD11b+Ly6G-CX3CR1highPD-L1lowcells obtained from SC of EAE mice treated with either IFN-γ or PBS
 
Contributor(s) Tichauer JE, Arellano G, Acuña E, González LF, Kannaiyan NR, Mirgas P, Panadero C, Ibañez-Vega J, Burgos PI, Loda E, Miller SD, Rossner MJ, Gebicke-Haerter PJ, Naves R
Citation(s) 37334380
Submission date May 06, 2023
Last update date Apr 29, 2024
Contact name Moritz J Rossner
E-mail(s) moritz.rossner@med.uni-muenchen.de
Organization name Lud.-Max.-University
Department Psychiatry
Lab Molecular Neurobiology
Street address Nussbaumstr. 7
City Munich
ZIP/Postal code 80336
Country Germany
 
Platforms (1)
GPL18635 Ion Torrent Proton (Mus musculus)
Samples (10)
GSM7304636 PBS Treated Replicate 1
GSM7304637 IFNg Treated Replicate 1
GSM7304638 PBS Treated Replicate 2
Relations
BioProject PRJNA968000

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Supplementary file Size Download File type/resource
GSE231833_rawCounts.txt.gz 538.4 Kb (ftp)(http) TXT
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Processed data are available on Series record

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