The phase dependent role of myeloid cells on direct inflammation and demyelination of the optic nerve and indirect retinal neuro- and axonal degeneration in experimental optic neuritis

• Applicants: Professor Dr. Philipp Albrecht; Professor Patrick Küry, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519640199

New therapeutic approaches preventing the chronic progression of disability or promoting repair in Multiple Sclerosis (MS) are warranted. Such approaches can be tested in optic neuritis (ON) as prototypical example for an acute inflammatory event in MS and its animal model experimental autoimmune encephalomyelitis (EAE). In EAE, autoreactive T cells inflitrate the central nervous system, where they recruit myeloid lineage cells. While infiltrating monocyte-derived macrophages drive disease pathogenesis, the contribution of resident microglia during the different disease phases is still not completely understood. Both, detrimental and beneficial effects have been attributed to the resident microglia in EAE. In the remission phase, microglia may play an important role in regulating immune functions and facilitating repair and remyelination, ultimately, preventing chronic neurodegeneration. At the same time, chronic microglial activation may very well drive demyelination and neuroaxonal loss during later progressive phases. To investigate these mechanisms, clinical severity scores and histologic end-point measurements are likely to be insufficient. Instead, highly sensitive assessments for neuroaxonal structure/function and microglial status allowing longitudinal in vivo measurements are required. Optical coherence tomography (OCT) is a non-invasive, technique allowing high resolution imaging of the eye’s retina in patients and mice. This makes OCT an ideal tool for visualizing neuroaxonal damage and neuronal loss during ON in MS and EAE. Using confocal scanning laser ophthalmoscopy (cSLO) we can image GFP labelled microglia in CX3CR1-GFP transgenic mice in vivo and monitor the highly efficient depletion of myeloid cells by treatment with pexidartinib, a CSF-1R antagonist. Additionally, we will assess direct demyelination in and inflammation in the optic nerve by histology and RNA sequencing. We hypothesize that microglia are essential mediators of inflammation induced neurodegeneration but also conversely relevant for remyelination and repair during ON. We aim to investigate the role of microglia and their influence on direct demyelination in the optic nerve and indirect retinal neurodegeneration and visual function in acute and chronic models of EAE as well as toxic demyelination by in vivo cSLO imaging of retinal microglia and by depleting microglia at different time points of disease using pexidartinib. We will use single cell RNA sequencing and immunohistochemistry to further investigate the role of the different cell types for the different aspects of damage, remyelination and repair. This research is of utmost clinical relevance as it will elucidate the role of myeloid cells for structural functional damage during ON, using readouts that can be transferred to a clinical trials scenario.

• DFG Programme: Research Grants