Interferon-gamma ameliorates experimental autoimmune encephalomyelitis by inducing homeostatic adaptation of microglia

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dc.contributor.authorTichauer, Juan E.
dc.contributor.authorArellano, Gabriel
dc.contributor.authorAcuna, Eric
dc.contributor.authorGonzalez, Luis F.
dc.contributor.authorKannaiyan, Nirmal R.
dc.contributor.authorMurgas, Paola
dc.contributor.authorPanadero-Medianero, Concepcion
dc.contributor.authorIbanez-Vega, Jorge
dc.contributor.authorBurgos, Paula I.
dc.contributor.authorLoda, Eileah
dc.contributor.authorMiller, Stephen D.
dc.contributor.authorRossner, Moritz J.
dc.contributor.authorGebicke-Haerter, Peter J.
dc.contributor.authorNaves, Rodrigo
dc.date.accessioned2025-01-20T20:10:17Z
dc.date.available2025-01-20T20:10:17Z
dc.date.issued2023
dc.description.abstractCompelling evidence has shown that interferon (IFN)-gamma 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-gamma 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-gamma 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-gamma 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 the spinal cord of IFN-gamma-treated EAE mice that were ex vivo re-stimulated with a low dose (1 ng/ml) of IFN-gamma and neuroantigen, promoted a significantly higher induction of CD4(+) regulatory T (Treg) cells associated with increased transforming growth factor (TGF)-beta secretion. Additionally, IFN-gamma-treated primary MC/MG cultures produced significantly lower nitrite in response to LPS challenge than control MC/MG. IFN-gamma-treated EAE mice had a significantly higher frequency of CX3CR1(high) MC/MG and expressed lower levels of program death ligand 1 (PD-L1) than PBS-treated mice. Most CX3CR1(high)PD-L1(low)CD11b(+)Ly6G(-) cells expressed MG markers (Tmem119, Sall2, and P2ry12), indicating that they represented an enriched MG subset (CX3CR1(high)PD-L1(low) MG). Amelioration of clinical symptoms and induction of CX3CR1(high)PD-L1(low) MG by IFN-gamma were dependent on STAT-1. RNA-seq analyses revealed that in vivo treatment with IFN-gamma promoted the induction of homeostatic CX3CR1(high)PD-L1(low) 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-gamma plays in regulating microglial activity and provide new insights into the cellular and molecular mechanisms involved in the therapeutic activity of IFN-gamma in EAE.
dc.fuente.origenWOS
dc.identifier.doi10.3389/fimmu.2023.1191838
dc.identifier.issn1664-3224
dc.identifier.urihttps://doi.org/10.3389/fimmu.2023.1191838
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/92058
dc.identifier.wosidWOS:001008567100001
dc.language.isoen
dc.revistaFrontiers in immunology
dc.rightsacceso restringido
dc.subjectmultiple sclerosis
dc.subjectexperimental autoimmune encephalomyelitis
dc.subjectinterferon-gamma
dc.subjectmicroglia
dc.subjectmyeloid cells
dc.subjectneuroinflammation
dc.subjectneurodegenerative disease
dc.subjectimmune tolerance
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleInterferon-gamma ameliorates experimental autoimmune encephalomyelitis by inducing homeostatic adaptation of microglia
dc.typeartículo
dc.volumen14
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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