BST W901 and VA Pittsburgh Healthcare System 1W139, 1W140, 1W143
Severe trauma and hemorrhage render the patient more susceptible to a second, seemingly trivial, inflammatory stimulus, the so-called “two-hit” hypothesis. The post-trauma sepsis, which involves activation of innate immunity, can lead to severe multi-organ failure (MOF) or systemic inflammatory response syndrome (SIRS), and death. Studies have suggested that cell priming caused by a first hit is the mechanism for enhanced response of the cell to a second hit.
Polymorphonuclear neutrophils (PMN) are essential effector cells of the innate immune system. The accumulation of PMN in tissue is considered a critical event in organ inflammation and injury, and has been the target of preventative strategies. PMN migration is a result of a cascade of cellular events, in which PMN, endothelial cells (EC), epithelia, and macrophages (MΦ) act in concert. Studies from Dr. Fan’s lab explored interrelated novel findings indicating that receptor cross-talk mechanisms occurring in PMN, EC, and MΦ are important determinants for augmenting PMN migration in a setting of SIRS. In PMN, LPS through Toll-like receptor (TLR)4 and phosphoinositide 3-kinase Υ signaling down-regulates the expression of G protein-coupled receptor kinases (GRK)2 and GRK5 in response to chemokine, and the reduced expression of GRKs decreases chemokine receptor desensitization and markedly augments the PMN migration response. However, in EC and MΦ, LPS/TLR4 signaling up-regulates TLR2, and oxidant signaling derived from PMN NADPH oxidase enhances the TLR2 upregulation through PMN-EC or PMN-MΦ interaction, and results in an amplified expression of adhesion molecules in the EC and release of cytokines and chemokines from the MΦ in response to TLR2 ligands, thereby promotes PMN migration. Furthermore, Dr. Fan’s lab demonstrated that hemorrhagic shock is potent to activate PMN NADPH oxidase through high-mobility group box 1 (HMGB1) -TLR4 - p38 MAPK signaling, and therefore initiates the mechanisms of cell priming. Taken together, receptor cross-talk mechanisms are critical determinants for cell priming and subsequent augmented PMN migration in sepsis.
The ongoing research projects in Dr. Fan’s lab include several lines that aim to elucidate the mechanisms of hemorrhagic shock-induced activation of inflammasome, pyroptosome, and autophagy in innate immune cells, as well as the significances of the resultant alterations in the development of post-hemorrhage SIRS.
Xu J, Jiang Y, Wang J, Shi X, Liu Q, Liu Z, Li Y, Scott MJ, Xiao G, Li S, Fan L, Billiar TR, Wilson MA, and Fan J. Macrophage Endocytosis of High Mobility Group Box 1 Triggers Pyroptosis. Cell Death and Differentiation 2014.4 (Advance online publication)
Xu P, Wen Z, Shi X, Li Y, Fan L, Xiang M, Li A, Scott M J, Xiao G, Li S, Billiar TR, Wilson MA, and Fan J. Hemorrhagic Shock Augments Nlrp3 Inflammasome Activation in the Lung through Impaired Pyrin Induction. J. Immunol. 2013, 190(10):5247.
Liu Z, Jiang Y, Li Y, Wang J, Fan L, Scott MJ, Xiao G, Li S, Billiar TR, Wilson MA, and Fan J. TLR4 Signaling Augments Monocyte Chemotaxis by Regulating G ProteinCoupled Receptor Kinase 2 Translocation. J. Immunol. 2013, 191 (2): 857.
Sun Q, Gao W, Loughran P, Shapiro R, Fan J, Billiar TR, Scott MJ. Caspase-1 activation is protective against hepatocyte cell death by up-regulating beclin1 and mitochondrial autophagy in the setting of redox stress. J Biol Chem. 2013, 288(22):15947.
Xiang M, Shi X, Li Y, Xu J, Yin L, Xiao G, Scott MJ, Billiar TR, Wilson MA, Fan J. Hemorrhagic Shock Activation of NLRP3 Inflammasome in Lung Endothelial Cells. J. Immunol. 2011, 187:4809-4817.
Xiang M, Yin L, Li Y, Xiao G, Vodovotz Y, Billiar TR, Wilson MA, and Fan J. Hemorrhagic Shock Activates Lung Endothelial NAD(P)H Oxidase Via Neutrophil NADPH Oxidase. Am. J. Respir. Cell Mol. Biol. 2011, 44(3):333-40.
Xiang M and Fan J. Pattern Recognition Receptor-Dependent Mechanisms of Acute Lung Injury. Molecular Medicine 2010,16(1-2):69-82.
Yujian Liu, Youzhong Yuan, Yuehua Li, Jian Zhang, Guozhi Xiao, Yoram Vodovotz, Timothy R. Billiar, Mark A. Wilson, and Fan J. Interacting Neuro-endocrine, Innate, and Acquired Immune Pathways Regulate Neutrophil Mobilization from Bone Marrow following Hemorrhagic Shock. J. Immunol. 2009，182:572-580,
Fan J and Malik AB. Toll-like receptor 4 signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nature Medicine 2003, 9(3): 315.
Fan J, RS Frey, and AB Malik. TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase. J. Clin. Invest. 2003, 112:1234-1243.