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

Frontiers in Immunology

Immunology

Concepción Panadero-Medianero¹  Paola Murgas¹  Paula I. Burgos²  Stephen D. Miller³  Eileah Loda³  Moritz J. Rossner⁴  Nirmal R. Kannaiyan⁴  Luis F. González⁵  Rodrigo Naves⁵  Jorge Ibañez-Vega⁵  Eric Acuña⁵  Juan E. Tichauer⁵  Peter J. Gebicke-Haerter⁶  Gabriel Arellano⁷ 

[1] Center for Integrative Biology, Faculty of Science, Universidad Mayor, Santiago, Chile;Department of Clinical Immunology and Rheumatology , School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile;Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States;Molecular Neurobiology, Department of Psychiatry & Psychotherapy, Ludwig-Maximilians-University of Munich, Munich, Germany;Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile;Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile;Central Institute of Mental Health, Faculty of Medicine, University of Heidelberg, Mannheim, Germany;Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile;Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States;

关键词: multiple sclerosis;    experimental autoimmune encephalomyelitis;    interferon-gamma;    microglia;    myeloid cells;    neuroinflammation;    neurodegenerative disease;    immune tolerance.;   

DOI  :  10.3389/fimmu.2023.1191838

 received in 2023-03-22, accepted in 2023-05-16,  发布年份 2023

来源: Frontiers

【 摘 要 】

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 the 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.

【 授权许可】

Unknown   
Copyright © 2023 Tichauer, Arellano, Acuña, González, Kannaiyan, Murgas, Panadero-Medianero, Ibañez-Vega, Burgos, Loda, Miller, Rossner, Gebicke-Haerter and Naves