title: Modulation of experimental arthritis by vagal sensory and central brain stimulation.
abstract: Articular inflammation is a major clinical burden in multiple inflammatory diseases, especially in rheumatoid arthritis. Biological anti-rheumatic drug therapies are expensive and increase the risk of systemic immunosuppression, infections, and malignancies. Here, we report that vagus nerve stimulation controls arthritic joint inflammation by inducing local regulation of innate immune response. Most of the previous studies of neuromodulation focused on vagal regulation of inflammation via the efferent peripheral pathway toward the viscera. Here, we report that vagal stimulation modulates arthritic joint inflammation through a novel "afferent" pathway mediated by the locus coeruleus (LC) of the central nervous system. Afferent vagal stimulation activates two sympatho-excitatory brain areas: the paraventricular hypothalamic nucleus (PVN) and the LC. The integrity of the LC, but not that of the PVN, is critical for vagal control of arthritic joint inflammation. Afferent vagal stimulation suppresses articular inflammation in the ipsilateral, but not in the contralateral knee to the hemispheric LC lesion. Central stimulation is followed by subsequent activation of joint sympathetic nerve terminals inducing articular norepinephrine release. Selective adrenergic beta-blockers prevent the effects of articular norepinephrine and thereby abrogate vagal control of arthritic joint inflammation. These results reveals a novel neuro-immune brain map with afferent vagal signals controlling side-specific articular inflammation through specific inflammatory-processing brain centers and joint sympathetic innervations.
authors.affiliation: Department of Immunology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil. Electronic address: shimizug@gmail.com.
authors.forename: Gabriel Shimizu
authors.initials: GS
authors.lastname: Bassi
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Daniel Penteado Martins
authors.initials: DPM
authors.lastname: Dias
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Franchin
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Jhimmy
authors.initials: J
authors.lastname: Talbot
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Daniel Gustavo
authors.initials: DG
authors.lastname: Reis
authors.affiliation: Center for Gastrointestinal Biology, Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Gustavo Batista
authors.initials: GB
authors.lastname: Menezes
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Jaci Airton
authors.initials: JA
authors.lastname: Castania
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Norberto
authors.initials: N
authors.lastname: Garcia-Cairasco
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Leonardo Barbosa Moraes
authors.initials: LBM
authors.lastname: Resstel
authors.affiliation: Department of Physiology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Helio Cesar
authors.initials: HC
authors.lastname: Salgado
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Fernando Queiróz
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Thiago Mattar
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Surgery, Center of Immunology & Inflammation, Rutgers-New Jersey Medical School, Rutgers University, Newark, NJ 07101, USA. Electronic address: Luis.Ulloa@Rutgers.edu.
authors.forename: Luis
authors.initials: L
authors.lastname: Ulloa
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil; Department of Physiological Sciences, Federal University of São Carlos, São Carlos, SP, Brazil. Electronic address: alex_bioquimica@yahoo.com.br.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kanashiro
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000344:Afferent Pathways / Q000503:physiopathology; D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000503:physiopathology / Q000628:therapy; D004558:Electric Stimulation; D008125:Locus Coeruleus / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000503:physiopathology*; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000235:genetics; D055536:Vagus Nerve Stimulation
chemical_list: D000319:Adrenergic beta-Antagonists; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse
keywords: Arthritis; Neuroimmune interactions; Neuroimmunomodulation; Neutrophil migration; Sympathetic nervous system; Vagus nerve