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Free keywords:
Acetylcholine/pharmacology/physiology
Animals
Animals, Congenic
Astrocytes/drug effects/metabolism
Brain Injuries/immunology/physiopathology
Butyrylcholinesterase/physiology
Cells, Cultured
Central Nervous System/chemistry/*metabolism/pathology
Cholinergic Fibers/*physiology
*Complement Activation
Complement C1q/biosynthesis/genetics
Complement C3/*biosynthesis/genetics
Denervation
Forkhead Transcription Factors/metabolism
Gene Expression Regulation/*immunology
*Gene Regulatory Networks
Genetic Linkage
Genome-Wide Association Study
Male
Mice
Mice, Inbred C57BL
Microglia/drug effects/metabolism
Quantitative Trait Loci
Rats
Rhizotomy
Specific Pathogen-Free Organisms
Spinal Nerve Roots/surgery
Synaptophysin/analysis
Tumor Necrosis Factor-alpha/pharmacology/physiology
Abstract:
The complement system is activated in a wide spectrum of CNS diseases and is suggested to play a role in degenerative phenomena such as elimination of synaptic terminals. Still, little is known of mechanisms regulating complement activation in the CNS. Loss of synaptic terminals in the spinal cord after an experimental nerve injury is increased in the inbred DA strain compared with the PVG strain and is associated with expression of the upstream complement components C1q and C3, in the absence of membrane attack complex activation and neutrophil infiltration. To further dissect pathways regulating complement expression, we performed genome-wide expression profiling and linkage analysis in a large F2(DA x PVG) intercross, which identified quantitative trait loci regulating expression of C1qa, C1qb, C3, and C9. Unlike C1qa, C1qb, and C9, which all displayed distinct coregulation with different cis-regulated C-type lectins, C3 was regulated in a coexpression network immediately downstream of butyrylcholinesterase. Butyrylcholinesterase hydrolyses acetylcholine, which exerts immunoregulatory effects partly through TNF-alpha pathways. Accordingly, increased C3, but not C1q, expression was demonstrated in rat and mouse glia following TNF-alpha stimulation, which was abrogated in a dose-dependent manner by acetylcholine. These findings demonstrate new pathways regulating CNS complement expression using unbiased mapping in an experimental in vivo system. A direct link between cholinergic activity and complement activation is supported by in vitro experiments. The identification of distinct pathways subjected to regulation by naturally occurring genetic variability is of relevance for the understanding of disease mechanisms in neurologic conditions characterized by neuronal injury and complement activation.
