@article {Hulse12199, author = {Raymond E. Hulse and Wade G. Swenson and Phillip E. Kunkler and David M. White and Richard P. Kraig}, title = {Monomeric IgG Is Neuroprotective via Enhancing Microglial Recycling Endocytosis and TNF-α}, volume = {28}, number = {47}, pages = {12199--12211}, year = {2008}, doi = {10.1523/JNEUROSCI.3856-08.2008}, publisher = {Society for Neuroscience}, abstract = {In brain, monomeric immunoglobin G (IgG) is regarded as quiescent and only poised to initiate potentially injurious inflammatory reactions via immune complex formation associated with phagocytosis and tumor necrosis factor α (TNF-α) production in response to disease. Using rat hippocampal slice and microglial cultures, here we show instead that physiological levels (i.e., 0.2{\textendash}20 μg/ml) of monomeric IgG unassociated with disease triggered benign low-level proinflammatory signaling that was neuroprotective against CA1 area excitotoxicity and followed a U-shaped or hormetic dose{\textendash}response. The data indicate that physiological IgG levels activated microglia by enhancing recycling endocytosis plus TNF-α release from these cells to produce the neuroprotection. Minocycline, known for its anti-inflammatory and neuroprotective effects when given after disease onset, abrogated IgG-mediated neuroprotection and related microglial effects when given before injury. In contrast, E-prostanoid receptor subtype 2 (EP2) activation, which served as an exemplary paracrine stimulus like the one expected from neuronal activity, amplified IgG-mediated increased microglial recycling endocytosis and TNF-α production. Furthermore, like monomeric IgG these EP2 related effects took days to be effective, suggesting both were adaptive anabolic effects consistent with those seen from other long-term preconditioning stimuli requiring de novo protein synthesis. The data provide the first evidence that brain monomeric IgG at physiological levels can have signaling function via enhanced recycling endocytosis/TNF-α production from microglia unassociated with disease and that these IgG-mediated changes may be a means by which paracrine signaling from neuronal activity influences microglia to evoke neuroprotection. The data provide further support that low-level proinflammatory neural immune signaling unassociated with disease enhances brain function.}, issn = {0270-6474}, URL = {https://www.jneurosci.org/content/28/47/12199}, eprint = {https://www.jneurosci.org/content/28/47/12199.full.pdf}, journal = {Journal of Neuroscience} }