Cholinergic neural signals to the spleen down-regulate leukocyte trafficking via CD11b.
The cholinergic anti-inflammatory pathway is a physiological mechanism that inhibits cytokine production and diminishes tissue injury during inflammation. Recent studies demonstrate that cholinergic signaling reduces adhesion molecule expression and chemokine production by endothelial cells and suppresses leukocyte migration during inflammation. It is unclear how vagus nerve stimulation regulates leukocyte trafficking because the vagus nerve does not innervate endothelial cells. Using mouse models of leukocyte trafficking, we show that the spleen, which is a major point of control for cholinergic modulation of cytokine production, is essential for vagus nerve-mediated regulation of neutrophil activation and migration. Administration of nicotine, a pharmacologic agonist of the cholinergic anti-inflammatory pathway, significantly reduces levels of CD11b, a beta(2)-integrin involved in cell adhesion and leukocyte chemotaxis, on the surface of neutrophils in a dose-dependent manner and this function requires the spleen. Similarly, vagus nerve stimulation significantly attenuates neutrophil surface CD11b levels only in the presence of an intact and innervated spleen. Further mechanistic studies reveal that nicotine suppresses F-actin polymerization, the rate-limiting step for CD11b surface expression. These studies demonstrate that modulation of leukocyte trafficking via cholinergic signaling to the spleen is a specific, centralized neural pathway positioned to suppress the excessive accumulation of neutrophils at inflammatory sites. Activating this mechanism may have important therapeutic potential for preventing tissue injury during inflammation.
Huston
Jared M
JM
The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
Rosas-Ballina
Mauricio
M
Xue
Xiangying
X
Dowling
Oonagh
O
Ochani
Kanta
K
Ochani
Mahendar
M
Yeboah
Michael M
MM
Chatterjee
Prodyot K
PK
Tracey
Kevin J
KJ
Metz
Christine N
CN
D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D002351:Carrageenan / Q000502:physiology; D002464:Cell Migration Inhibition / Q000276:immunology*; D018679:Cholinergic Agonists / Q000008:administration & dosage*; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000008:administration & dosage; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000294:innervation*; D013156:Splenectomy; D014630:Vagus Nerve / Q000276:immunology
D039481:CD11b Antigen; D018679:Cholinergic Agonists; D018836:Inflammation Mediators; D009538:Nicotine; D002351:Carrageenan