Uncovering the roles of proinflammatory cytokine signaling in NG2-glia cells during neuroinflammation and demyelination

• Applicant: Dr. Maja Papic, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497430190

Multiple sclerosis (MS) is the most common autoimmune demyelinating disease of the central nervous system (CNS) that predominantly affects young adults. Despite a certain success of immunomodulating therapies in slowing the disease progression, a definitive cure is still lacking. Much less advancement has been made in the promotion of myelin repair around denuded axons (remyelination), which would target a direct cause of neurological deficits. One promising approach in that direction would be to enhance the maturation of oligodendrocyte precursor cells (OPCs), also known as NG2-glia, a cell population abundantly present in the adult CNS. However, a growing body of evidence suggests that NG2-glia do not serve only as oligodendrocyte replacement cells, but directly participate in the pathogenesis of MS. Therefore, elucidating the response of these cells to the tissue damage and inflammatory mediators produced during the course of neuroinflammation is a crucial step in development of new therapies.Our preliminary data demonstrated that NG2+ cells of the CNS express immune-response associated molecules that can modulate the pathology of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Conditional deletion of the interleukin (IL-1) signaling specifically in NG2+ cells lead to impaired recovery after EAE induction. This was accompanied by the increased number of OPCs and enhanced expression of MHC class II molecules by these cells. Furthermore, we showed that IL-1 decreased the expression of OPC-specific genes and that the effects of IL-1 were particularly strong in the presence of interferon-gamma (IFN-γ). In the proposed project, we aim to elucidate the role of two key cytokines associated with MS and EAE pathogenesis, IL-1 and IFN-γ, in modulating the fate and function of NG2-glia during neuroinflammation and demyelination. For that, we will conditionally delete cytokine receptors specifically in NG2-glia and investigate the effects in two different experimentally induced pathological contexts, reflecting different aspects of MS pathogenesis: autoinflammation and demyelinating injury. By applying in vitro and in vivo models and cutting-edge techniques such as single-cell transcriptomics, we will obtain more conceptual insights into the function of these cells and their diversity in health and disease. With the proposed project, we aim to dissect the molecular mechanisms involved in remyelination and immunomodulation processes, which will provide the foundations for development of urgently needed treatments for inflammatory demyelinating diseases of the CNS.

• DFG Programme: Research Grants