Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR I and TLR4 pathways

Abstract

Oxidative and immune attacks from the environment or microglia have been implicated in the loss of dopaminergic neurons of Parkinson's disease. The role of IgG which is an important immunologic molecule in the process of Parkinson's disease has been unclear. Evidence suggests that IgG can be produced by neurons in addition to its traditionally recognized source B lymphocytes, but its function in neurons is poorly understood. In this study, extensive expression of neuron-derived IgG was demonstrated in dopaminergic neurons of human and rat mesencephalon. With an in vitro Parkinson's disease model, we found that neuron-derived IgG can improve the survival and reduce apoptosis of dopaminergic neurons induced by 6-hydroxydopamine toxicity, and also depress the release of NO from microglia triggered by 6-hydroxydopamine. Expression of TNF-α and IL-10 in microglia was elevated to protective levels by neuron-derived IgG at a physiologic level via the FcγR I and TLR4 pathways and microglial activation could be attenuated by IgG blocking. All these data suggested that neuron-derived IgG may exert a self-protective function by activating microglia properly, and IgG may be involved in maintaining immunity homeostasis in the central nervous system and serve as an active factor under pathological conditions such as Parkinson's disease.

Keywords: 3-amino-9-ethyl-carbazole; 6-OHDA; 6-hydroxydopamine; AEC; CNPase; CNS; DA; Fc gamma receptor I; Fc gamma receptors; FcγR I; FcγRI; FcγRs; GFAP; HMGB1; HRP; IGHG1; IHC; ISH; IgG heavy chain; Igκ; Iγ-Cγ; Iγ-Cγ sterile germ line transcripts; LCM; LPS; Microglia; Neuron-derived IgG; PD; Parkinson's disease; RAG1/2; SN; SNc; TH; TLR4; central nervous system; cyclic nucleotide 3′-phosphohydrolase; dopaminergic; glial fibrillary acidic protein; hVLJH; high mobility group box 1; horseradish peroxidase; immunoglobulin kappa chain; immunohistochemistry; in situ hybridization; laser capture microdissection; lipopolysaccharide; pars compacta of the substantia nigra; recombination activating gene 1/2; substantia nigra; tyrosine hydroxylase; variable region of heavy chain.