1 PhD project offered in the IPP winter call 2022
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) with unknown etiology. In addition to immune cells, recent data suggest that cells of the oligodendrocyte lineage can also directly contribute to the CNS inflammation in MS. In line with that, NG2-glia (oligodendrocyte precursor cells) were found to be main responders to the encephalitogenic interleukin-17 cytokine in the CNS. Furthermore, others and we demonstrated that the presence of NG2 proteoglycan itself is necessary for development of neuroinflammation . Recently, it was reported that oligodendrocyte heterogeneity increases in MS and that some disease-specific subclusters display immune cell signature. In addition, oligodendrocyte precursors were found to express antigen presenting apparatus and were able to phagocytose and present antigens to CD4+ and CD8+ T cells in experimental models of neuroinflammatory diseases.
PhD Project: The role of interferon-gamma signaling in NG2-glia during experimental autoimmune encephalomyelitis
Our laboratory has been studying extensively various aspects of MS pathogenesis, from the immune system activation at the periphery, to the events occurring at the CNS level [2-6]. In the frame of the present project, we will focus on the role of interferon-gamma (IFN-g), one of the key cytokines involved in MS pathogenesis, in modulating the fate and function of NG2-glia. Previous studies demonstrated that IFN-g blocks OPC differentiation and induces expression of molecules involved in antigen presentation. Here, we will apply various mouse models and cutting-edge techniques to investigate NG2 glia-specific IFN-g signaling in the context of experimentally induced neuroinflammation.
The presented project will provide a deeper understanding of the role of oligodendrocyte precursor cells (OPCs) in neuroinflammation. We aim to identify molecules, affected by IFN-g signaling, with possible roles in immune function and/ or progression to mature oligodendrocyte stages, which could then be subjected to pharmacological or genetic manipulation for a potential therapeutic intervention. In addition to identifying molecular mechanisms of IFN-g action in OPCs, the project will provide more conceptual insights into the function of these cells and their diversity in neuroinflammation.
Publications relevant to this project
Kitic, M., et al., NG2 plays a role in neuroinflammation but is not expressed by immune cells. Acta Neuropathologica, 2017. 134(2): p. 325-327.
Hovelmeyer, N., et al., Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. J Immunol, 2005. 175(9): p. 5875-84.
Locatelli, G., et al., Primary oligodendrocyte death does not elicit anti-CNS immunity. Nat Neurosci, 2012. 15(4): p. 543-50.
Mufazalov, I.A., et al., IL‐1 signaling is critical for expansion but not generation of autoreactive GM‐CSF+ Th17 cells. The EMBO Journal, 2017. 36(1): p. 102-115.
Hauptmann, J., et al., Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood-brain barrier. Acta Neuropathol, 2020. 140(4): p. 549-567.
Frommer, F., et al., Tolerance without clonal expansion: self-antigen-expressing B cells program self-reactive T cells for future deletion. J Immunol, 2008. 181(8): p. 5748-59.