Abstract
Cholinergic neural output has been shown to modulate innate immune responses to infection, injury and ischemia through stimulation of α7 nicotinic acetylcholine receptors (α7nAChR) on mononuclear phagocytes. We tested the hypothesis that cholinergic neurotransmitters, similar to those released through activation of a neural reflex, regulate responses to products of the adaptive immune system, specifically immune complex (IC)-mediated activation of effector cells. In this study, we show that stimulation of α7nAChR on human polymorphonuclear neutrophils (PMNs) and blood mononuclear phagocytes in vitro attenuates C5aR- and FcγR-triggered generation of reactive oxygen species, expression of leukocyte markers involved in cell recruitment and adhesion, and release of TNF-α and other proinflammatory cytokines. We show that this pathway is operative in vivo. Ligation of cholinergic receptors blunts IC-triggered responses in the reverse peritoneal Arthus reaction in mice. The selective 7nAChR agonist GTS21 decreased PMN accumulation and release of cytokines and chemokines at sites of IC deposition. In addition, mice lacking α7nAChR had exaggerated responses to reverse peritoneal Arthus reaction characterized by increased infiltration of PMNs and elevated of levels of TNF-α and CXCL1 in peritoneal fluid compared with wild-type mice. Taken together, these findings suggest that cholinergic output has the potential to exert tonic inhibitory activity that dampens responses to ICs and C5a and thus may be a target to minimize tissue damage in autoimmune diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / pharmacology
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Animals
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Ascitic Fluid / chemistry
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Ascitic Fluid / immunology
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Benzylidene Compounds / pharmacology
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Cell Adhesion / drug effects
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Cells, Cultured
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Chemokine CXCL1 / biosynthesis
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Chemokine CXCL1 / genetics
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Chemotaxis, Leukocyte / drug effects
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Complement C5a / genetics
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Complement C5a / pharmacology
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Cytokines / metabolism
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Female
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Humans
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I-kappa B Kinase / metabolism
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Immune Complex Diseases / immunology*
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Inflammation
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neutrophils / drug effects
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Neutrophils / immunology*
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Nicotine / pharmacology
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Nicotinic Agonists / pharmacology
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Phagocytes / drug effects
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Phagocytes / immunology*
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Phosphorylation / drug effects
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Protein Processing, Post-Translational / drug effects
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Pyridines / pharmacology
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Reactive Oxygen Species / metabolism
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Receptor, Anaphylatoxin C5a / antagonists & inhibitors
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Receptors, IgG / antagonists & inhibitors
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Recombinant Proteins / pharmacology
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Respiratory Burst / drug effects
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Respiratory Burst / physiology
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Specific Pathogen-Free Organisms
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alpha7 Nicotinic Acetylcholine Receptor / agonists
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alpha7 Nicotinic Acetylcholine Receptor / immunology*
Substances
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Benzylidene Compounds
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Chemokine CXCL1
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Chrna7 protein, human
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Chrna7 protein, mouse
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Cxcl1 protein, mouse
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Cytokines
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Nicotinic Agonists
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Pyridines
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Reactive Oxygen Species
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Receptor, Anaphylatoxin C5a
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Receptors, IgG
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Recombinant Proteins
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alpha7 Nicotinic Acetylcholine Receptor
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Nicotine
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Complement C5a
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3-(2,4-dimethoxybenzylidene)anabaseine
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I-kappa B Kinase
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Acetylcholine