Intra- and intercellular functions of redoxins during neuroinflammation

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Reversible oxidative thiol modifications are posttranslational modifications that control signal transduction making thiol switches of utmost significance for cellular functions. These switches are tightly regulated by redoxins - oxidoreductases of the thioredoxin family.In our proposal, we will address several aspects of this protein family that are still barely understood. We want to increase i) the number of characterized substrates and improve the understanding of ii) substrate specificity, iii) regulatory variety in addition to protein (in)activation, e.g. translocation or the interplay with other modifications, and the iv) spatio-temporal activity of redoxins, in particular extracellular functions of secreted redoxins. Based on our experiences in neurology and inflammation, we will synergistically analyze the functions of redoxins in neuroinflammation combining in vitro (cell cultures), ex vivo (primary cells, organotypic slice cultures), and in vivo models (zebrafish, mice) as well as samples from multiple sclerosis patients (brain slices, serum, cerebrospinal fluid). Within our two projects we will investigate redoxin-regulated processes and their underlying molecular mechanisms in glia cells during regeneration and immunomodulation. The regeneration from inflammation-induced brain damage and thereby the protection against neurological deficits depends on the migration of oligodendroglial progenitor cells towards lesions and their remyelinating capacity. We hypothesize that the identified glutaredoxin 2-induced differentiation block in a specific state (NG2-glia cells) enhances regeneration of neurons in different inflammation paradigms (autoimmunity, traumatic injury).To analyze the immunomodulatory mechanisms of secreted redoxins, we will investigate the secretion of redoxins by distinct cell types involved in neuroinflammation, in particular micro- and astroglia, and characterize their extracellular substrates and functions. Based on preliminary data, we propose secreted redoxins as new diagnostic tools for disease progression and effectiveness of immunomodulatory therapy which will be investigated by translating our findings to patients suffering from multiple sclerosis. In addition to the removal of oxidative thiol modifications by redoxins, we will also investigate the formation of these modifications on a mechanistic and physiologic level, focusing on the potential thiol oxidase lysine specific demethylase1. In summary, our two projects provide the first comprehensive investigation of redoxin functions in glial cells. Choosing the pathological condition of neuroinflammation, with emphasis on multiple sclerosis, our proposal will provide both translational results with direct clinical impact and fundamental mechanistic and functional insights into redoxins and redox regulation of intra- and intercellular signaling.