title: Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors.
abstract: Almost all degenerative diseases of the CNS are associated with chronic inflammation. A central step in this process is the activation of brain mononuclear phagocyte cells, called microglia. While it is recognized that healthy neurons and astrocytes regulate the magnitude of microglia-mediated innate immune responses and limit excessive CNS inflammation, the endogenous signals governing this process are not fully understood. In the peripheral nervous system, recent studies suggest that an endogenous 'cholinergic anti-inflammatory pathway' regulates systemic inflammatory responses via alpha 7 nicotinic acetylcholinergic receptors (nAChR) found on blood-borne macrophages. These data led us to investigate whether a similar cholinergic pathway exists in the brain that could regulate microglial activation. Here we report for the first time that cultured microglial cells express alpha 7 nAChR subunit as determined by RT-PCR, western blot, immunofluorescent, and immunohistochemistry analyses. Acetylcholine and nicotine pre-treatment inhibit lipopolysaccharide (LPS)-induced TNF-alpha release in murine-derived microglial cells, an effect attenuated by alpha 7 selective nicotinic antagonist, alpha-bungarotoxin. Furthermore, this inhibition appears to be mediated by a reduction in phosphorylation of p44/42 and p38 mitogen-activated protein kinase (MAPK). Though preliminary, our findings suggest the existence of a brain cholinergic pathway that regulates microglial activation through alpha 7 nicotinic receptors. Negative regulation of microglia activation may also represent additional mechanism underlying nicotine's reported neuroprotective properties.
authors.affiliation: Child Development Center, Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medciine, Tampa, Florida, USA.
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Shytle
authors.forename: Takashi
authors.initials: T
authors.lastname: Mori
authors.forename: Kirk
authors.initials: K
authors.lastname: Townsend
authors.forename: Martina
authors.initials: M
authors.lastname: Vendrame
authors.forename: Nan
authors.initials: N
authors.lastname: Sun
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Jared
authors.initials: J
authors.lastname: Ehrhart
authors.forename: Archie A
authors.initials: AA
authors.lastname: Silver
authors.forename: Paul R
authors.initials: PR
authors.lastname: Sanberg
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D002478:Cells, Cultured; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002038:Bungarotoxins; C579166:Chrna7 protein, mouse; D008070:Lipopolysaccharides; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000109:Acetylcholine