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Cholinergic Neural Signals to the Spleen Down-Regulate Leukocyte Trafficking via CD11b¹

Jared M. Huston^2,3,*, Mauricio Rosas-Ballina^3,*, Xiangying Xue, Oonagh Dowling, Kanta Ochani^*, Mahendar Ochani^*, Michael M. Yeboah^*, Prodyot K. Chatterjee, Kevin J. Tracey^* and Christine N. Metz^4,

^* Laboratory of Biomedical Sciences, The Feinstein Institute for Medical Research, Manhasset, NY 11030; and Laboratory of Medicinal Biochemistry, The Feinstein Institute for Medical Research, Manhasset, NY 11030

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 β₂-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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by The National Institute of General Medicine Sciences (R01 GM070727 to C.N.M. and R01 GM057226 to K.J.T.), The North Shore-Long Island Jewish Health System General Clinical Research Center (M01 RR018535, to K.J.T.), The American Heart Association (to C.N.M.), The North Shore-Long Island Jewish Health System (to C.N.M.), and the Elmezzi Graduate School of Molecular Medicine (to M.M.Y.).

² Current address: Weill-Cornell Medical Center, Department of Surgery, New York, NY 10021.

³ J.M.H. and M.R.-B. contributed equally to this manuscript.

⁴ Address correspondence and reprint requests to Dr. Christine N. Metz, Laboratory of Medicinal Biochemistry, The Susan and Herman Merinoff Center for Patient Oriented Research, 350 Community Drive, Manhasset, NY 11030. E-mail address: cmetz{at}nshs.edu

⁵ Abbreviations used in this paper: 7-nAChR, 7-nicotinic acetylcholine receptor; VNS, vagus nerve stimulation; CLP, cecal ligation and puncture; MFI, mean fluorescence intensity; HSP, heat shock protein.

⁶ The online version of this article contains supplemental material.