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Interacting Neuroendocrine and Innate and Acquired Immune Pathways Regulate Neutrophil Mobilization from Bone Marrow following Hemorrhagic Shock¹

Yujian Liu^*, Youzhong Yuan^*, Yuehua Li^*, Jian Zhang, Guozhi Xiao, Yoram Vodovotz^*, Timothy R. Billiar^*, Mark A. Wilson^*, and Jie Fan^2,*,

^* Department of Surgery, Department of Medicine, School of Medicine, University of Pittsburgh, and Surgical Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15213

Polymorphonuclear neutrophils (PMN) are critical innate immune effector cells that either protect the host or exacerbate organ dysfunction by migrating to injured or inflamed tissues. Resuscitated hemorrhagic shock following major trauma promotes the development of organ inflammation by priming PMN migration and activation in response to a second, often trivial, stimulus (a so-called "two hit" phenomenon). PMN mobilization from bone marrow supports a sustained, hemorrhagic shock/resuscitation (HS/R)-primed migration of PMN. We addressed the role and mechanism of HS/R in regulating PMN egress from bone marrow. We demonstrate that HS/R through the alarmin HMGB1 induces IL-23 secretion from macrophages in an autocrine and TLR4 signaling-dependent manner. In turn IL-23, through an IL-17 G-CSF-mediated mechanism, induces PMN egress from bone marrow. We also show that β-adrenergic receptor activation by catecholamine of macrophages mediates the HS/R-induced release of HMGB1. These data indicate that HS/R, a global ischemia/reperfusion stimulus, regulates PMN mobilization through a series of interacting pathways that include neuroendocrine and innate and acquired immune systems. Blocking this novel signaling axis may present a novel therapeutic target for posttrauma 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 Grant R01-HL-079669 from the National Institutes of Health (to J.F.), by Grant P50-GM-53789 from the National Institutes of Health Center (to T.R.B. and Y.V.), and by a Veterans Affairs Merit Award (to J.F.).

² Address correspondence and reprint requests to Dr. Jie Fan, Department of Surgery, Building 1, Room 2W109 (151L-U), Veterans Affairs Pittsburgh Healthcare System, University Drive C, Pittsburgh, PA 15240. E-mail address: jif7{at}pitt.edu

³ Abbreviations used in this paper: HS/R, hemorrhagic shock/resuscitation; AM, alveolar macrophage; BAL, bronchoalveolar lavage; I/R, ischemia/reperfusion; IRAK, IL-1R-associated kinase; PMN, polymorphonuclear neutrophil; WT wild type.