The Journal of Neuroscience, November 19, 2008, 28(47):12199-12211; doi:10.1523/JNEUROSCI.3856-08.2008
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Neurobiology of Disease
Monomeric IgG Is Neuroprotective via Enhancing Microglial Recycling Endocytosis and TNF-
Raymond E. Hulse,
Wade G. Swenson,
Phillip E. Kunkler,
David M. White, and
Richard P. Kraig
Department of Neurology, The University of Chicago Medical Center, Chicago, Illinois 60637
Correspondence should be addressed to Richard P. Kraig, Department of Neurology, MC2030, the University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637. Email: rkraig{at}neurology.bsd.uchicago.edu
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 
(TNF-) production in response to disease. Using rat hippocampal slice and microglial cultures, here we show instead that physiological levels (i.e., 0.2–20 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–response. The data indicate that physiological IgG levels activated microglia by enhancing recycling endocytosis plus TNF- 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- 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- 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.
Key words: cytokine; slice cultures; neuroprotection; neuroinflammation; hippocampus; endocytosis; hormesis
Received Aug. 13, 2008;
accepted Oct. 6, 2008.
Correspondence should be addressed to Richard P. Kraig, Department of Neurology, MC2030, the University of Chicago Medical Center, 5841 South Maryland Avenue, Chicago, IL 60637. Email: rkraig{at}neurology.bsd.uchicago.edu
