Autocrine control of neutrophil chemotaxis

Summary

Principal Investigator: W G Junger
Abstract: Chemotaxis allows polymorphonuclear neutrophils (PMN) to rapidly reach infected and inflamed sites. Despite recent progress in our understanding of chemotaxis, many open questions still remain. Chemoattractants stimulate the release of ATP from PMN and autocrine feedback loops via purinergic receptors control chemotaxis. In this project we revised the the scope of the proposed work to understand how the chemotactic signals induce ATP release and how adenosine formed from the released ATP controls negative feedback loops that play a critical role in defining cell polarity and uropod retraction. The proposed project rests on the following revised working hypothesis: Stimulation of chemoattractant receptors induces rapid intracellular events that result in ATP release. Additional ATP release through distinct mechanisms provides the ligand, adenosine, for suppressive A2a adenosine receptors. These receptors increases cAMP levels at the receding edge, providing an inhibitory feedback loop that elicits global inhibition and promotes uropod contraction, defining cell polarity and promoting migration. We propose to test this working hypothesis in by addressing the following Revised Specific Aims: Specific Aim 1. Upstream events leading to ATP release We will determine the upstream signaling pathways that link chemotactic receptor activation and ATP release during gradient sensing. In addition, we will examine different ATP release mechanisms and their contributions to ATP release during gradient sensing, cell polarization, and migration. Emphasis will be placed on the signaling pathway downstream of chemotactic receptors e.g., calcium signaling and MAPK activation that lead to the opening of ATP release channels such as connexins or pannexins and release of ATP via vesicular transport. Specific Aim 2. Global inhibition and purinergic signaling We will study if and how purinergic receptors, e.g., A2a or A2b adenosine receptors induce global inhibition that defines polarity and promotes cell migration. Emphasis will be placed on the suppressive down-stream signaling pathways that elicit global inhibition. We will focus on activation of adenylate cyclases, PKA, and cAMP accumulation. In addition, we will examine how these signaling events block gradient sensing and induce Rho activation and myosin formation that induces uropod contraction at the receding edge. Knowledge of these mechanisms will further define the purinergic mechanisms that control chemotaxis and may allow us to conceive novel therapeutic strategies aimed at treating these purinergic responses to treat inflammatory and infectious diseases.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Plasma ATP is required for neutrophil activation in a mouse sepsis model
    Yuka Sumi
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts Department of Emergency and Critical Care Medicine, Juntendo University, Urayasu Hospital, Chiba, Japan Department of Anesthesiology, Ludwig Maximilian University, Munich, Germany and Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
    Shock 42:142-7. 2014
  2. pmc Prehospital hypertonic saline resuscitation attenuates the activation and promotes apoptosis of neutrophils in patients with severe traumatic brain injury
    Wolfgang G Junger
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School and Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria Defence Research and Development Canada, Toronto Research Centre and Departments of Surgery and Critical Care Medicine, St Michael s Hospital, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Harborview Medical Center, University of Washington, Seattle, Washington Brain Injury Laboratory, Cara Phelan Centre for Trauma Research Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael s Hospital, University of Toronto, Toronto, Ontario, Canada and American College of Surgeons, Department of Surgery, University of California, Irvine, California
    Shock 40:366-74. 2013
  3. pmc Pannexin 1 channels link chemoattractant receptor signaling to local excitation and global inhibition responses at the front and back of polarized neutrophils
    Yi Bao
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 288:22650-7. 2013
  4. pmc Resuscitation of traumatic hemorrhagic shock patients with hypertonic saline-without dextran-inhibits neutrophil and endothelial cell activation
    Wolfgang G Junger
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School and Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
    Shock 38:341-50. 2012
  5. pmc ATP release and autocrine signaling through P2X4 receptors regulate γδ T cell activation
    Monali Manohar
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    J Leukoc Biol 92:787-94. 2012
  6. pmc Measurement of oxidative burst in neutrophils
    Yu Chen
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    Methods Mol Biol 844:115-24. 2012
  7. pmc Immune cell regulation by autocrine purinergic signalling
    Wolfgang G Junger
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    Nat Rev Immunol 11:201-12. 2011
  8. pmc Hypertonic stress regulates T cell function via pannexin-1 hemichannels and P2X receptors
    Tobias Woehrle
    Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
    J Leukoc Biol 88:1181-9. 2010
  9. pmc Adrenergic receptor activation involves ATP release and feedback through purinergic receptors
    Yuka Sumi
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    Am J Physiol Cell Physiol 299:C1118-26. 2010
  10. pmc A3 adenosine receptor inhibition improves the efficacy of hypertonic saline resuscitation
    Yoshiaki Inoue
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
    Shock 35:178-83. 2011

Scientific Experts

  • W G Junger
  • Yu Chen
  • Tobias Woehrle
  • Yuka Sumi
  • Yongli Yao
  • Yoshiaki Inoue
  • Yi Bao
  • Monali Manohar
  • Hiroshi Tanaka
  • Mark I Hirsh
  • Andrew Li
  • Linda Yip
  • Abdallah Elkhal
  • Xiaoou Li
  • Linglin Li
  • Carola Ledderose
  • Anjali A Karande
  • Paul A Insel
  • Qin Zhang
  • Uyen Kim To
  • Carl Hauser

Detail Information

Publications12

  1. pmc Plasma ATP is required for neutrophil activation in a mouse sepsis model
    Yuka Sumi
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts Department of Emergency and Critical Care Medicine, Juntendo University, Urayasu Hospital, Chiba, Japan Department of Anesthesiology, Ludwig Maximilian University, Munich, Germany and Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
    Shock 42:142-7. 2014
    ..However, increased PMN activation can also be detrimental by promoting secondary organ damage. We conclude that pharmacological targeting of P2 receptors may allow modulation of PMN responses in sepsis. ..
  2. pmc Prehospital hypertonic saline resuscitation attenuates the activation and promotes apoptosis of neutrophils in patients with severe traumatic brain injury
    Wolfgang G Junger
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School and Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria Defence Research and Development Canada, Toronto Research Centre and Departments of Surgery and Critical Care Medicine, St Michael s Hospital, University of Toronto, Toronto, Ontario, Canada Department of Surgery, Harborview Medical Center, University of Washington, Seattle, Washington Brain Injury Laboratory, Cara Phelan Centre for Trauma Research Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael s Hospital, University of Toronto, Toronto, Ontario, Canada and American College of Surgeons, Department of Surgery, University of California, Irvine, California
    Shock 40:366-74. 2013
    ..Since hypertonic fluids can inhibit PMN activation, we studied whether hypertonic fluid resuscitation can reduce excessive PMN activation in TBI patients...
  3. pmc Pannexin 1 channels link chemoattractant receptor signaling to local excitation and global inhibition responses at the front and back of polarized neutrophils
    Yi Bao
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 288:22650-7. 2013
    ..PANX1 channels thus link local excitatory signals to the global inhibitory signals that orchestrate chemotaxis of neutrophils in gradient fields. ..
  4. pmc Resuscitation of traumatic hemorrhagic shock patients with hypertonic saline-without dextran-inhibits neutrophil and endothelial cell activation
    Wolfgang G Junger
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School and Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria
    Shock 38:341-50. 2012
    ..These data suggest that hypertonic resuscitation without dextran may inhibit posttraumatic inflammation. However, despite this effect, neither HS nor HSD reduced MODS in trauma patients with hemorrhagic shock...
  5. pmc ATP release and autocrine signaling through P2X4 receptors regulate γδ T cell activation
    Monali Manohar
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    J Leukoc Biol 92:787-94. 2012
    ..Our data thus indicate that purinergic signaling via P2X4 receptors plays an important role in orchestrating the functional response of circulating human γδ T cells...
  6. pmc Measurement of oxidative burst in neutrophils
    Yu Chen
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    Methods Mol Biol 844:115-24. 2012
    ..The first method depends on the reduction of cytochrome c, which can be assessed by photometry, while the second method relies on changes in the fluorescence properties of dihydrorhodamine 123, which can be assessed by flow cytometry...
  7. pmc Immune cell regulation by autocrine purinergic signalling
    Wolfgang G Junger
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    Nat Rev Immunol 11:201-12. 2011
    ..This Review focuses on the roles of autocrine purinergic signalling in the regulation of both innate and adaptive immune responses and discusses the potential of targeting purinergic receptors for treating immune-mediated disease...
  8. pmc Hypertonic stress regulates T cell function via pannexin-1 hemichannels and P2X receptors
    Tobias Woehrle
    Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA
    J Leukoc Biol 88:1181-9. 2010
    ..We conclude that HS and P2 receptor agonists promote T cell function and thus, could be used to improve T cell function in trauma patients...
  9. pmc Adrenergic receptor activation involves ATP release and feedback through purinergic receptors
    Yuka Sumi
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
    Am J Physiol Cell Physiol 299:C1118-26. 2010
    ..We conclude that, like formyl peptide receptors, adrenergic receptors require purinergic feedback mechanisms to control complex physiological processes such as smooth muscle contraction and regulation of vascular tone...
  10. pmc A3 adenosine receptor inhibition improves the efficacy of hypertonic saline resuscitation
    Yoshiaki Inoue
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
    Shock 35:178-83. 2011
    ..Our data thus show that A3 receptor antagonists can strengthen the beneficial effects of HS resuscitation by avoiding stimulatory adverse effects that result from delayed HS administration...
  11. pmc Pannexin-1 hemichannel-mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse
    Tobias Woehrle
    Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
    Blood 116:3475-84. 2010
    ..We conclude that pannexin-1 hemichannels and P2X1 and P2X4 receptors facilitate ATP release and autocrine feedback mechanisms that control Ca(2+) entry and T-cell activation at the immune synapse...
  12. pmc Purinergic signaling: a fundamental mechanism in neutrophil activation
    Yu Chen
    Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
    Sci Signal 3:ra45. 2010
    ..Thus, purinergic signaling is a fundamental mechanism required for neutrophil activation and immune defense...