Project: B02

Role of macrophage-dependent osmoprotective and hypoxic signal transduction in inflammatory corneal diseases

Both O2 and Na+ are recognized as important regulators of immunity. The hypoxia-responsive signaling transduction and osmoprotective signaling pathways play a key role in adaptation to low O2 tensions and to increased Na+ levels. Moreover, both signaling pathways contribute to inflammatory outputs and impact the ability of macrophages to fight (skin) infections. In addition, both O2 and Na+ can impact skin hem- and lymphangiogenesis and might play a role in (neovascular) ocular surface diseases. Macrophages are important modulators of a variety of ocular surface diseases and play an important role in adaption of tissues to low O2 tensions and in response to increased tissue tonicity. The oxygen (O2)-responsive hypoxia-inducible factor (HIF)-prolyl hydroxylase domain (PHD) system, osmoprotective p38/MAPK activation and downstream NFAT5 play an important role in this respect. Furthermore, there is evidence that HIF stabilization can be increased by exposure to hypertonic conditions. Both regulatory systems may amplify inflammatory signaling of myeloid cells. Importantly, osmoprotective signaling can regulate lymphangiogenesis in skin.

Although the avascular cornea commonly suffers from hypoxic conditions and is in contact with the hyperosmolar tear film e.g. in dry eye disease, not much is known about the impact of the above-mentioned factors and signaling associated with low O2 and high tonicity in myeloid cells on inflammatory corneal diseases. Here, we will test the hypothesis that inflammatory neovascular corneal diseases result in modification of corneal Na+ and oxygen levels and that local modification of HIF/PHD and osmoprotective signaling via p38/MAPK bears therapeutic potential in treating inflammatory (neovascular) corneal diseases.

Key methods: in-vivo mouse models, ELISA, qRT-PCR, FACS sorting, histology, immunohistochemistry, cell culture, RNA-seq