The role of fibrinogen for T-cell recruitment in neuroinflammation.
Final Report Abstract
The role of CNS immunity in neurodegenerative disorders, such as the autoimmune demyelinating diseases Multiple Sclerosis (MS), is of growing relevance for the development of novel immunebased treatments. In human MS lesions, innate immune cells of different origin – resident microglia and peripherally derived macrophages – contribute to oxidative stress-induced neurotoxicity and autoimmune-driven neurodegeneration1-3. Blood-brain-barrier disruption and deposition of the blood protein fibrinogen inside the CNS has been identified are early pathological hallmarks that precede inflammatory demyelination and clinical symptoms4. In rodent models with neuroinflammation, fibrinogen triggers innate and adoptive immune responses inside the CNS5,6. Here, I used state-of-the-art imaging technologies and genome-wide transcriptomics to addressed how fibrin(ogen)-triggered immune cell recruitment and interactions are linked to autoimmune and neurotoxic mechanisms during neuroinflammation. In this study I used the experimental autoimmune encephalomyelitis (EAE) model in combination with acute in vivo two-photon imaging for real-time tracing of Tcells and interactions with antigen-presenting cells (APCs), including activated microglia and infiltrating macrophages, in the spinal cord of fluorescent reporter mouse lines. Neurotoxicity was assessed by ex vivo imaging and histology of axonal damage. The findings contribute to our working hypothesis that fibrin(ogen)-induced clustering of microglia and macrophages activates Tcell-mediated autoimmune response and direct neurotoxicity. Ongoing imaging experiments will validate fibrinogen-dependent effects of Tcell interactions with activated microglia and/or infiltrating macrophages. A striking observation of functionally distinct microglia and macrophage populations in EAE lesions led to the development of a sorting assay for genome-wide transcriptome profiling of autoimmune and neurotoxic signatures. RNA-Sequencing and computational analysis revealed profound heterogeneity between microglia/macrophages with specific immune and neurotoxic signatures. Screening these expression profiles, molecular targets have been identified, which might selectively inhibit innate immune cells, while preserving beneficial functions of other innate immune subsets during CNS inflammation.
Publications
- (2016) Finding the 'ubiquitous' threads in infection and autoimmune neuroinflammation. Nature immunology 18 (1) 7–8
Bardehle, Sophia; Rafalski, Victoria; Akassoglou, Katerina
(See online at https://doi.org/10.1038/ni.3633) - “Breaking boundaries—Coagulation and fibrinolysis at the neurovascular interface”, in Front. Cell. Neurosci. (2015); 16(9):354
Bardehle S, Rafalski V, Akassoglou K
(See online at https://doi.org/10.3389/fncel.2015.00354)
