title: Monomeric IgG is neuroprotective via enhancing microglial recycling endocytosis and TNF-alpha.
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 alpha (TNF-alpha) production in response to disease. Using rat hippocampal slice and microglial cultures, here we show instead that physiological levels (i.e., 0.2-20 microg/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-alpha 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-alpha 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-alpha 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.
authors.affiliation: Department of Neurology, The University of Chicago Medical Center, Chicago, Illinois 60637, USA.
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Hulse
authors.forename: Wade G
authors.initials: WG
authors.lastname: Swenson
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Kunkler
authors.forename: David M
authors.initials: DM
authors.lastname: White
authors.forename: Richard P
authors.initials: RP
authors.lastname: Kraig
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D053331:Ectodysplasins / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus; D000860:Hypoxia; D007074:Immunoglobulin G / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000502:physiology*; D008911:Minocycline / Q000494:pharmacology; D016202:N-Methylaspartate / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D009924:Organ Culture Techniques; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D015232:Dinoprostone; D053331:Ectodysplasins; D005947:Glucose; D007074:Immunoglobulin G; D053583:Interleukin-1beta; D052118:Lysosomal-Associated Membrane Protein 1; D008911:Minocycline; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010751:Phosphopyruvate Hydratase; D014409:Tumor Necrosis Factor-alpha; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins