title: Infiltration of CCR2+Ly6Chigh Proinflammatory Monocytes and Neutrophils into the Central Nervous System Is Modulated by Nicotinic Acetylcholine Receptors in a Model of Multiple Sclerosis.
abstract: Myeloid cells, including proinflammatory monocytes and neutrophils, have important roles in the pathology of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). These cells infiltrate the CNS in the early stages of disease development and contribute to the inflammatory response that is associated with symptom severity. It is thus crucial to identify and understand new mechanisms that can regulate the CNS infiltration of proinflammatory myeloid cells. Nicotinic acetylcholine receptors (nAChRs) have been increasingly studied for their immune-regulatory properties. In this study, we assessed the ability of nicotine, an nAChR ligand, to modulate proinflammatory myeloid cell numbers within the bone marrow, spleen, blood, and CNS of EAE mice. We found that nicotine significantly inhibits the infiltration of proinflammatory monocytes and neutrophils into the CNS at time points where these cells are known to play critical roles in disease pathology. In contrast, nicotine does not affect the expansion of other monocytes. We also show that nicotine exerts these effects by acting on α7 and α9 nAChR subtypes. Finally, mRNA transcript levels for CCL2 and CXCL2, chemokines involved in the chemotaxis of proinflammatory monocytes and neutrophils, respectively, are reduced in the brain of nicotine-treated EAE mice before the massive infiltration of these cells. Taken together, our data provide evidence that nAChRs can regulate proinflammatory cell infiltration into the CNS, which could be of significant value for the treatment of neuroinflammatory disorders.
authors.affiliation: Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, Heping District 300052, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Département de Chimie et Biochimie, Université de Moncton, Moncton, New Brunswick E1A 3E9, Canada;
authors.forename: Stéphanie
authors.identifier: http://orcid.org/0000-0001-5235-6285
authors.initials: S
authors.lastname: St-Pierre
authors.affiliation: Département de Chimie et Biochimie, Université de Moncton, Moncton, New Brunswick E1A 3E9, Canada;
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0001-8050-1697
authors.initials: P
authors.lastname: Roy
authors.affiliation: Boys Town National Research Hospital, Omaha, NE 68131; and.
authors.forename: Barbara J
authors.identifier: http://orcid.org/0000-0001-5268-8845
authors.initials: BJ
authors.lastname: Morley
authors.affiliation: Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, Heping District 300052, China; alain.simard@umoncton.ca hjw@tijmu.edu.cn.
authors.forename: Junwei
authors.initials: J
authors.lastname: Hao
authors.affiliation: Département de Chimie et Biochimie, Université de Moncton, Moncton, New Brunswick E1A 3E9, Canada; Centre de Formation Médicale du Nouveau-Brunswick, Moncton, New Brunswick E1A 3E9, Canada alain.simard@umoncton.ca hjw@tijmu.edu.cn.
authors.forename: Alain R
authors.identifier: http://orcid.org/0000-0002-3499-6235
authors.initials: AR
authors.lastname: Simard
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D001921:Brain / Q000276:immunology; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D009103:Multiple Sclerosis / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000276:immunology; D011978:Receptors, Nicotinic / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000276:immunology
chemical_list: D000950:Antigens, Ly; C515335:Ccr2 protein, mouse; C494192:Ly-6C antigen, mouse; D018722:Nicotinic Agonists; D054390:Receptors, CCR2; D011978:Receptors, Nicotinic; D009538:Nicotine
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