The role of fibrinogen for T-cell recruitment in neuroinflammation.

• Applicant: Dr. Sophia Bardehle
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264677378

Multiple Sclerosis (MS) is a chronic neuroinflammatory disorder of the central nervous system (CNS) that is characterized by demyelination and axonal damage, as well as progressive motor dysfunction. While immunological processes during MS pathology are well-described, the etiology of MS lesions remains unknown. To identify early molecular factors that trigger neuroinflammatory demyelination, we need a better understanding of the neurovascular niche including the contribution of blood-brain barrier (BBB) disruption to the development of the neuroinflammatory lesions. The Akassoglou laboratory has made the novel discovery that during BBB disruption, the plasma fibrinogen leakage leads to perivascular clustering and activation of microglia via CD11b/CD18 integrin receptor signaling. Fibrinogen, a critical component of blood coagulation, extravasates across a damaged BBB and accumulates as fibrin deposits at specific sites of injury. The widespread deposition of fibrin within the nervous system is well documented in demyelinating plaques in MS. Genetic or pharmacologic depletion of fibrinogen or genetic disruption of fibrinogen binding to CD11b reduces activation of the innate immune response and neurological signs in Experimental Autoimmune Encephalomyelitis (EAE), an animal model for human MS. While these findings implicate important regulatory functions of extravascular fibrinogen on CNS innate immune responses, the effects of fibrinogen on adaptive immunity during neuroinflammation remain largely unknown. We hypothesize that fibrinogen interaction with the CD11b/CD18 integrin receptor, which is expressed in innate immune cells, regulates T cell activation and their recruitment into the CNS. To test this hypothesis, I will employ a multifaceted experimental design to determine the role of fibrinogen in T cell trafficking and activation in the CNS. The first aim of this proposal is to use state-of-the-art in vivo imaging techniques to address the role of fibrinogen on T-cell trafficking and subsequent parenchymal cell-cell interactions in demyelinating spinal cord lesions in EAE. Taking advantage of two-photon microscopy for fluorescent live cell imaging in vivo, I will monitor the behavior of myelin-specific T cells in the spinal cord of EAE-induced mice. In the second aim I will investigate the intracellular signaling cascade linking fibrinogen/CD11b/CD18-induced activation of antigen presenting cells (APC) with adaptive immune responses. Overall, these findings will revolutionize our understanding of the cellular mechanisms and molecular determinants that link neuroinflammation, demyelination and BBB functions. Identifying the mechanisms of fibrin actions in the nervous system could ultimately illuminate new therapeutic strategies for the treatment of MS.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Katerina Akassoglou, Ph.D.