title: Unbiased expression mapping identifies a link between the complement and cholinergic systems in the rat central nervous system.
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 × 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-α pathways. Accordingly, increased C3, but not C1q, expression was demonstrated in rat and mouse glia following TNF-α 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.
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden;
authors.forename: Rickard P F
authors.initials: RP
authors.lastname: Lindblom
authors.forename: Mikael
authors.initials: M
authors.lastname: Ström
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinig
authors.forename: Faiez
authors.initials: F
authors.lastname: Al Nimer
authors.forename: Shahin
authors.initials: S
authors.lastname: Aeinehband
authors.forename: Alexander
authors.initials: A
authors.lastname: Berg
authors.forename: Cecilia A
authors.initials: CA
authors.lastname: Dominguez
authors.forename: Swetha
authors.initials: S
authors.lastname: Vijayaraghavan
authors.forename: Xing-Mei
authors.initials: XM
authors.lastname: Zhang
authors.forename: Karin
authors.initials: K
authors.lastname: Harnesk
authors.forename: Johan
authors.initials: J
authors.lastname: Zelano
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.forename: Staffan
authors.initials: S
authors.lastname: Cullheim
authors.forename: Taher
authors.initials: T
authors.lastname: Darreh-Shori
authors.forename: Margarita
authors.initials: M
authors.lastname: Diez
authors.forename: Fredrik
authors.initials: F
authors.lastname: Piehl
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D020296:Animals, Congenic; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000276:immunology / Q000503:physiopathology; D002091:Butyrylcholinesterase / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D002799:Cholinergic Fibers / Q000502:physiology*; D003167:Complement Activation; D015922:Complement C1q / Q000096:biosynthesis / Q000235:genetics; D003176:Complement C3 / Q000096:biosynthesis* / Q000235:genetics; D003714:Denervation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D053263:Gene Regulatory Networks; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D040641:Quantitative Trait Loci; D051381:Rats; D019051:Rhizotomy; D013047:Specific Pathogen-Free Organisms; D013126:Spinal Nerve Roots / Q000601:surgery; D016708:Synaptophysin / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology
chemical_list: D003176:Complement C3; D051858:Forkhead Transcription Factors; D016708:Synaptophysin; C569016:Syp protein, rat; D014409:Tumor Necrosis Factor-alpha; C070635:interleukin binding factor; D015922:Complement C1q; D002091:Butyrylcholinesterase; D000109:Acetylcholine