title: Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia.
abstract: The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit alpha7, a mechanism termed "the cholinergic antiinflammatory pathway." Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of alpha7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiac-superior mesenteric plexus, and projecting in the splenic nerve.
authors.affiliation: Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rosas-Ballina
authors.forename: Mahendar
authors.initials: M
authors.lastname: Ochani
authors.forename: William R
authors.initials: WR
authors.lastname: Parrish
authors.forename: Kanta
authors.initials: K
authors.lastname: Ochani
authors.forename: Yael T
authors.initials: YT
authors.lastname: Harris
authors.forename: Jared M
authors.initials: JM
authors.lastname: Huston
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Chavan
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000276:immunology*; D004558:Electric Stimulation; D019446:Endotoxemia / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009538:Nicotine / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000294:innervation*; D048069:Tumor Necrosis Factors / Q000276:immunology*; D014630:Vagus Nerve / Q000276:immunology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D048069:Tumor Necrosis Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine