Anti-HMGB1 Monoclonal Antibody Ameliorates Immunosuppression after Peripheral Tissue Trauma: Attenuated T-Lymphocyte Response and Increased Splenic CD11b+Gr-1+ Myeloid-Derived Suppressor Cells Require HMGB1

Although tissue-derived high mobility group box 1 (HMGB1) is involved in many aspects of inflammation and tissue injury after trauma, its role in trauma-induced immune suppression remains elusive. Using an established mouse model of peripheral tissue trauma, which includes soft tissue and fracture components, we report here that treatment with anti-HMGB1 monoclonal antibody ameliorated the trauma-induced attenuated T-cell responses and accumulation of CD11b+Gr-1+ myeloid-derived suppressor cells in the spleens seen two days after injury. Our data suggest that HMGB1 released after tissue trauma contributes to signaling pathways that lead to attenuation of T-lymphocyte responses and enhancement of myeloid-derived suppressor cell expansion.

[1]  H. Baker,et al.  Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma , 2014, The journal of trauma and acute care surgery.

[2]  Y. Vodovotz,et al.  The Central Role of Arginine Catabolism in T-Cell Dysfunction and Increased Susceptibility to Infection After Physical Injury , 2014, Annals of surgery.

[3]  K. Tao,et al.  HMGB1 recruits myeloid derived suppressor cells to promote peritoneal dissemination of colon cancer after resection. , 2013, Biochemical and biophysical research communications.

[4]  K. Tracey,et al.  The many faces of HMGB1: molecular structure‐functional activity in inflammation, apoptosis, and chemotaxis , 2013, Journal of leukocyte biology.

[5]  T. Billiar,et al.  Selective roles for toll-like receptors 2, 4, and 9 in systemic inflammation and immune dysfunction following peripheral tissue injury , 2013, The journal of trauma and acute care surgery.

[6]  H. Baker,et al.  Identification and Description of a Novel Murine Model for Polytrauma and Shock , 2013, Critical care medicine.

[7]  S. Singhal,et al.  Myeloid derived suppressor cells , 2013, Oncoimmunology.

[8]  T. Billiar,et al.  Inducible Nitric Oxide Synthase Contributes to Immune Dysfunction Following Trauma , 2012, Shock.

[9]  J. Lederer,et al.  Trauma equals danger—damage control by the immune system , 2012, Journal of leukocyte biology.

[10]  G. Hong,et al.  Up-regulation of mitofusin-2 protects CD4+ T cells from HMGB1-mediated immune dysfunction partly through Ca(2+)-NFAT signaling pathway. , 2012, Cytokine.

[11]  Kevin W Eliceiri,et al.  NIH Image to ImageJ: 25 years of image analysis , 2012, Nature Methods.

[12]  John D. Storey,et al.  A genomic storm in critically injured humans , 2011, The Journal of experimental medicine.

[13]  M. Tsan.  Heat shock proteins and high mobility group box 1 protein lack cytokine function , 2011, Journal of leukocyte biology.

[14]  T. Billiar,et al.  Pseudofracture: an acute peripheral tissue trauma model. , 2011, Journal of visualized experiments : JoVE.

[15]  Y. Vodovotz,et al.  Models of lower extremity damage in mice: time course of organ damage and immune response. , 2011, The Journal of surgical research.

[16]  K. Tracey,et al.  HMGB1 is a therapeutic target for sterile inflammation and infection. , 2011, Annual review of immunology.

[17]  L. Su,et al.  Interleukin-6 Induces Gr-1+CD11b+ Myeloid Cells to Suppress CD8+ T Cell-Mediated Liver Injury in Mice , 2011, PloS one.

[18]  Lyle L. Moldawer,et al.  A Paradoxical Role for Myeloid-Derived Suppressor Cells in Sepsis and Trauma , 2011, Molecular medicine.

[19]  T. Billiar,et al.  Role of hemorrhage in the induction of systemic inflammation and remote organ damage: Analysis of combined pseudo‐fracture and hemorrhagic shock , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[20]  A. Epstein,et al.  Characterization of Cytokine-Induced Myeloid-Derived Suppressor Cells from Normal Human Peripheral Blood Mononuclear Cells , 2010, The Journal of Immunology.

[21]  J. Magarian Blander,et al.  Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function , 2010, The Journal of experimental medicine.

[22]  J. Solomkin,et al.  Divergent adaptive and innate immunological responses are observed in humans following blunt trauma , 2010, BMC Immunology.

[23]  J. Ochoa,et al.  Stat 6-Dependent Induction of Myeloid Derived Suppressor Cells After Physical Injury Regulates Nitric Oxide Response to Endotoxin , 2010, Annals of surgery.

[24]  Yanghua Qin,et al.  HMGB1 Enhances the Proinflammatory Activity of Lipopolysaccharide by Promoting the Phosphorylation of MAPK p38 through Receptor for Advanced Glycation End Products1 , 2009, The Journal of Immunology.

[25]  E. Abraham.  Unraveling the role of high mobility group box protein 1 in severe trauma , 2009, Critical care.

[26]  I. Chaudry,et al.  Suppression of activation and costimulatory signaling in splenic CD4+ T cells after trauma-hemorrhage reduces T-cell function: a mechanism of post-traumatic immune suppression. , 2009, The American journal of pathology.

[27]  U. Andersson,et al.  The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation , 2009, Journal of leukocyte biology.

[28]  A. Sauaia,et al.  HMGB1 IS MARKEDLY ELEVATED WITHIN 6 HOURS OF MECHANICAL TRAUMA IN HUMANS , 2009, Shock.

[29]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[30]  F. Schade,et al.  Invited review: Deterioration of the immune system after trauma: signals and cellular mechanisms , 2008, Innate immunity.

[31]  D. Foell,et al.  Proinflammatory S100 Proteins Regulate the Accumulation of Myeloid-Derived Suppressor Cells1 , 2008, The Journal of Immunology.

[32]  I. Chaudry,et al.  Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations , 2008, Molecular medicine.

[33]  E. Abraham,et al.  HMGB1 Develops Enhanced Proinflammatory Activity by Binding to Cytokines1 , 2008, The Journal of Immunology.

[34]  J. Leips,et al.  Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. , 2007, Cancer research.

[35]  L. Moldawer,et al.  MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis , 2007, The Journal of experimental medicine.

[36]  L. Audoly,et al.  Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE , 2007, Nature Immunology.

[37]  D. Angus,et al.  Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis* , 2007, Critical care medicine.

[38]  H. Rauvala,et al.  Analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin) , 2007, Journal of leukocyte biology.

[39]  M. Bianchi.  Interview with Dr. Heikki Rauvala regarding Pivotal Advance: Analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin) , 2007, Journal of leukocyte biology.

[40]  I. Chaudry,et al.  Lidocaine depresses splenocyte immune functions following trauma-hemorrhage in mice. , 2006, American journal of physiology. Cell physiology.

[41]  O. Levy,et al.  TCR ζ Down-Regulation under Chronic Inflammation Is Mediated by Myeloid Suppressor Cells Differentially Distributed between Various Lymphatic Organs1 , 2006, The Journal of Immunology.

[42]  K. Tracey,et al.  Anti-HMGB1 Neutralizing Antibody Ameliorates Gut Barrier Dysfunction and Improves Survival after Hemorrhagic Shock , 2006, Molecular medicine.

[43]  J. Ochoa,et al.  CD11b+/Gr-1+ Myeloid Suppressor Cells Cause T Cell Dysfunction after Traumatic Stress1 , 2006, The Journal of Immunology.

[44]  M. Keel,et al.  Pathophysiology of polytrauma. , 2005, Injury.

[45]  I. Chaudry,et al.  Transgenic prolactin-/- mice: effect of trauma-hemorrhage on splenocyte functions. , 2005, American journal of physiology. Cell physiology.

[46]  K. Tracey,et al.  The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion , 2005, The Journal of experimental medicine.

[47]  B. Fingleton,et al.  Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. , 2004, Cancer cell.

[48]  Haichao Wang,et al.  Bench to bedside: HMGB1-a novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department. , 2004, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.

[49]  J. Puyana,et al.  Both T-helper-1- and T-helper-2-type lymphokines are depressed in posttrauma anergy. , 1998, The Journal of trauma.

[50]  F. Schildberg,et al.  Postburn constitutional changes in T-cell reactivity occur in CD8+ rather than in CD4+ cells. , 1997, The Journal of trauma.

[51]  A. Kelso.  Th1 and Th2 subsets: paradigms lost? , 1995, Immunology today.

[52]  J. Mannick,et al.  Altered Gene Transcription After Burn Injury Results in Depressed T‐Lymphocyte Activation , 1994, Annals of surgery.

[53]  J. L. Rodriguez,et al.  Lymphocyte subset responses to trauma and sepsis. , 1993, The Journal of trauma.

[54]  S. Jonjić,et al.  Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes , 1989, The Journal of experimental medicine.

[55]  A. Munster.  POST-TRAUMATIC IMMUNOSUPPRESSION IS DUE TO ACTIVATION OF SUPPRESSOR T CELLS , 1976, The Lancet.

[56]  Anne S Frankel,et al.  National Institutes of Health , 2019, The Grants Register 2022.

[57]  C. Divino,et al.  Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. , 2010, Cancer research.

[58]  L. Audoly,et al.  Toll-like receptor 9 – dependent activation by DNA-containing immune complexes is mediated by HMGB 1 and RAGE , 2007 .

[59]  A. Sauaia,et al.  Epidemiology of trauma deaths: a reassessment. , 1993, The Journal of trauma.

[60]  J. Lenihan,et al.  Staff-location systems suitable for hospital use. , 1958, Lancet.