GPR183 is not a key regulator of microglial inflammation Alex Delbridge1, Jeremy Burns1, Adam Bero1, Cherie Butts1, Michael Mingueneau1 1Biogen, Cambridge, MA, USA
Loci associated with microglia function have been identified with high confidence in genetic analyses of Alzheimer's disease (GWAS), and have been implicated in other neurodegenerative and neuroinflammatory diseases. GPR183 is very highly expressed in mouse and human microglia and the rate limiting enzyme for synthesis of its cognate ligand is dynamically regulated under disease conditions. Furthermore this pathway is important during humoral and anti-viral immunity in the periphery. We sought to determine the importance of GPR183-dependent signaling in the manifestation of disease processes. Based on available expression profiling data, GPR183-deficient mice were interrogated in several in vivo models with differing neuroinflammatory features; LPS-induced inflammation, cuprizone-induced demyelination, SOD1G93A Tg induced neuronal cell death. We found no evidence of involvement of GPR183 in microglia-driven neuroinflammation in the models tested. Supporting data failed to reveal any downstream transcriptional targets of ligand mediated-GPR183 activation, despite robust receptor engagement. The disconnect between maintenance of very high levels of GPR183 and our inability to determine a biological role for this receptor is puzzling and warrants further investigation in other contexts.
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