The blockade of neuropilin-2 as a new therapeutic principle in arthritis

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In rheumatoid arthritis (and also in colitis) we observed repulsion of sympathetic nerve fibres in inflamed tissue. Sympathetic neurotransmitters in high concentrations exert antiinflammatory effects. Thus, their loss probably aggravates inflammation. In previous work, funded by the DFG, we were able to identify two probable causes of repulsion of sympathetic nerve fibres, so-called nerve repellent factors: These are semaphorin 3C (SEMA3C) and placental growth factor (PlGF) from human synovial macrophages and fibroblasts. Expression of SEMA3C is significantly increased in patients with rheumatoid arthritis as compared to osteoarthritis or trauma controls. It is known that SEMA3C, PlGF, and VEGF165 all bind the promiscuous nerve repellent factor receptor neuropilin-2 on sympathetic nerve terminals. Thus, blockade of only one particular nerve repellent factor may be without any effect in vivo (redundancy). It is the main goal in this project to neutralise neuropilin-2, and to study the effects of inhibition of this important receptor in vitro and in vivo. Besides the generation of antibodies against neuropilin-2 for immunohistochemistry in human and murine tissue, a soluble neuropilin-2 Fc-fusion construct will be generated. The neutralising effect of this Fc-fusion construct will be tested in the nerve outgrowth assay. This construct will be further used in an animal model of arthritis. In extension of this study in arthritis, we will demonstrate the impact of nerve fibre repulsion in cutaneous wound healing and dextrane sulphate - induced colitis in mice.