MONOKINE GENE EXPRESSION/REGULATION IN LUNG INJURY

Summary

Principal Investigator: STEVEN LYNN KUNKEL
Abstract: The early events of severe sepsis set in motion a cascade of mechanisms, which significantly contribute to both the acute and chronic morbidity and mortality associated with this syndrome. While sepsis has often been viewed as a deadly acute disease, it also has insidious long-term consequences. Clinical data underscores the high mortality rates associated with patients who are long-term survivors of the acute septic episode. Within eight years of surviving severe sepsis, there is an 80% predicted mortality rate, with many patients succumbing to cancer and inflammatory lung complications. In this revised, renewal application we will expand our previous investigations of acute systemic disease and focus on the cellular and molecular mechanisms which cause sepsis-induced long-term immune dysregulation. We have established an experimental model of severe sepsis (cecal ligation and puncture-CLP) which results in a long-term survival rate of approximately 60%. Our preliminary studies have demonstrated that these CLP survivors are susceptible to an innocuous microbe challenge with high mortality weeks after recovery, while 100% of the sham animals survive. The mechanism for the lingering susceptibility appears related to the initial depletion of DC populations and the subsequent "re-seeding" of tissue by impaired DCs that have undergone epigenetic changes, altering cytokine expression. We hypothesize that the long-term consequences of severe sepsis are caused by altered dendritic cell populations, as innate and acquired immune functions of re-seeded bone marrow-derived dendritic cells are modified via novel mechanisms, including epigenetic modifications, contributing to the altered immune functions that follows severe sepsis. Our studies will focus on the following Specific Aims: 1) To identify the contribution of dendritic cell subsets to the general pathology, cytokine expression, and alterations in immune cell function in long-term survivors of mild (90% survivors) and severe (50-60% survivors) experimental sepsis. 2) To determine the mechanism(s) responsible for the immunoregulation found in long-term survivors of severe sepsis by assessing novel mechanisms, including epigenetic modifications, that affect the expression of key immune cell-derived cytokine genes, and 3) To develop efficacious therapies to restore dendritic cell function after severe sepsis via adoptive cell transfer strategies and the pharmacologic targeting of epigenetic alterations. PUBLIC HEALTH RELEVANCE: Sepsis is a severe, life threatening disease that can affect multiple organs in the body. This disease is usually described as an acute disorder, but recent clinical studies have shown that there are medical consequences, which last for years after patients are released from the intensive care unit. We have experimentally modeled the long-term effects of severe sepsis and have uncovered important mechanisms that lead to impaired immune cell function associated with the chronic aspect of this disease.
Funding Period: 1984-01-01 - 2013-12-31
more information: NIH RePORT

Top Publications

  1. ncbi Absence of CC chemokine receptor 8 enhances innate immunity during septic peritonitis
    Akihiro Matsukawa
    Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
    FASEB J 20:302-4. 2006
  2. pmc The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth
    Karen A Cavassani
    Department of Pathology, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    Blood 115:4403-11. 2010
  3. pmc IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis
    Kenneth Lyn-Kew
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Michigan Medical School, Ann Arbor, Michigan, United States of America
    PLoS ONE 5:e11145. 2010
  4. pmc Delta-like 4 differentially regulates murine CD4 T cell expansion via BMI1
    Matthew A Schaller
    Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 5:e12172. 2010
  5. pmc Epigenetic regulation of immune cell functions during post-septic immunosuppression
    William F Carson
    Department of Pathology, University of Michigan, Ann Arbor, USA
    Epigenetics 6:273-83. 2011
  6. pmc CCR6 as a mediator of immunity in the lung and gut
    Toshihiro Ito
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    Exp Cell Res 317:613-9. 2011
  7. pmc Critical role for CXC ligand 10/CXC receptor 3 signaling in the murine neonatal response to sepsis
    Alex G Cuenca
    Departments of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, Florida 32610 0286, USA
    Infect Immun 79:2746-54. 2011
  8. pmc Dysregulated cytokine expression by CD4+ T cells from post-septic mice modulates both Th1 and Th2-mediated granulomatous lung inflammation
    William F Carson
    Department of Pathology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 6:e20385. 2011
  9. pmc The critical role of Notch ligand Delta-like 1 in the pathogenesis of influenza A virus (H1N1) infection
    Toshihiro Ito
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
    PLoS Pathog 7:e1002341. 2011
  10. pmc MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function
    Ryoko Shimizu-Hirota
    Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA
    Genes Dev 26:395-413. 2012

Research Grants

  1. Suppression of T cell immunity during sepsis
    Thomas S Griffith; Fiscal Year: 2013

Detail Information

Publications32

  1. ncbi Absence of CC chemokine receptor 8 enhances innate immunity during septic peritonitis
    Akihiro Matsukawa
    Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
    FASEB J 20:302-4. 2006
    ..Altogether, these results indicate that CCR8 may have a negative impact on host defense during septic peritonitis, providing a new paradigm for the role of CCR8 in innate immunity...
  2. pmc The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth
    Karen A Cavassani
    Department of Pathology, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    Blood 115:4403-11. 2010
    ..Together, these data show that the post septic immune system obstructs tumor immunosurveillance, in part, by augmented Treg expansion and function...
  3. pmc IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis
    Kenneth Lyn-Kew
    Division of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Michigan Medical School, Ann Arbor, Michigan, United States of America
    PLoS ONE 5:e11145. 2010
    ..Our findings indicate that systemic sepsis induces epigenetic silencing of cytokine gene expression in lung macrophages, and IRAK-M appears to be a critical mediator of this response...
  4. pmc Delta-like 4 differentially regulates murine CD4 T cell expansion via BMI1
    Matthew A Schaller
    Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 5:e12172. 2010
    ..It has also been shown that Notch ligands have diverse functions during T cell activation. We chose to investigate the role of Notch ligands during the Th2 response...
  5. pmc Epigenetic regulation of immune cell functions during post-septic immunosuppression
    William F Carson
    Department of Pathology, University of Michigan, Ann Arbor, USA
    Epigenetics 6:273-83. 2011
    ..This review will discuss important pathways of immune cell activation affected by severe sepsis, and highlight pathways of epigenetic regulation that may be involved in post-septic immunosuppression...
  6. pmc CCR6 as a mediator of immunity in the lung and gut
    Toshihiro Ito
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    Exp Cell Res 317:613-9. 2011
    ..Herein, we summarize the role of CCR6 in immune responses at epithelial and mucosal sites in both the lung and gut based on a review of the current literature...
  7. pmc Critical role for CXC ligand 10/CXC receptor 3 signaling in the murine neonatal response to sepsis
    Alex G Cuenca
    Departments of Surgery, University of Florida College of Medicine and Dentistry, Gainesville, Florida 32610 0286, USA
    Infect Immun 79:2746-54. 2011
    ..Together, these data suggest a critical role for CXCL10 signaling during neonatal sepsis...
  8. pmc Dysregulated cytokine expression by CD4+ T cells from post-septic mice modulates both Th1 and Th2-mediated granulomatous lung inflammation
    William F Carson
    Department of Pathology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 6:e20385. 2011
    ..These results suggest that cell-intrinsic defects in CD4+ T cell effector function can have deleterious effects on inflammatory processes post-sepsis, due to a defect in the proper regulation of TH-specific cytokine expression...
  9. pmc The critical role of Notch ligand Delta-like 1 in the pathogenesis of influenza A virus (H1N1) infection
    Toshihiro Ito
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
    PLoS Pathog 7:e1002341. 2011
    ....
  10. pmc MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function
    Ryoko Shimizu-Hirota
    Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA
    Genes Dev 26:395-413. 2012
    ..These findings identify a novel role for nuclear MT1-MMP as a previously unsuspected transactivator of signaling networks central to macrophage immune responses...
  11. pmc Notch system in the linkage of innate and adaptive immunity
    Toshihiro Ito
    Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
    J Leukoc Biol 92:59-65. 2012
    ..In the present review, we discuss recent findings that explore the mechanisms underlying the role of Notch signaling in the linkage of innate and adaptive immunity, including pulmonary infection though PPRs and Notch activation...
  12. pmc CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis
    Makoto Ishii
    Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160 8582, Japan
    J Immunol 188:5655-64. 2012
    ..Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis...
  13. pmc STAT3-mediated IL-17 production by postseptic T cells exacerbates viral immunopathology of the lung
    Sumanta Mukherjee
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
    Shock 38:515-23. 2012
    ..Taken together, these data provide evidence that postseptic CD4 T cells are primed toward IL-17 production via increased STAT3-mediated gene transcription, which may contribute to the immunopathology of a secondary viral infection...
  14. pmc Toll like receptor 3 plays a critical role in the progression and severity of acetaminophen-induced hepatotoxicity
    Karen A Cavassani
    Department of Pathology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 8:e65899. 2013
    ..e. nMuLi). Moreover, TLR3 activation enhanced the expression of phosphorylated JNK in APAP injured livers. Thus, the current study demonstrates that TLR3 activation contributes to APAP-induced hepatotoxicity...
  15. pmc Impaired CD4+ T-cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis
    William F Carson
    Department of Pathology, University of Michigan, Ann Arbor, MI 48105, USA
    Eur J Immunol 40:998-1010. 2010
    ....
  16. pmc Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells
    JiHoon Chang
    Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Proc Natl Acad Sci U S A 106:18327-32. 2009
    ..e., ubiquitination and protein degradation. Thus, a previously undescribed regulatory mechanism by which IL-10-mediated protein degradation contributes to the inhibition of inflammatory cytokine production and endotoxin tolerance in DC...
  17. pmc Severe sepsis exacerbates cell-mediated immunity in the lung due to an altered dendritic cell cytokine profile
    Haitao Wen
    Department of Pathology, University of Michigan Medical School, M5214 Med Sci I, 1301 Catherine St, Ann Arbor, MI 48109 0602, USA
    Am J Pathol 168:1940-50. 2006
    ..Our data indicate that severe sepsis shifts the pulmonary cytokine environment, presumably via effects on pulmonary dendritic cells, which in turn alters the lung cell-mediated immune response...
  18. pmc CCR4 participation in Th type 1 (mycobacterial) and Th type 2 (schistosomal) anamnestic pulmonary granulomatous responses
    Christine M Freeman
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48105, USA
    J Immunol 177:4149-58. 2006
    ..Therefore, CCR4 is not Th2-restricted and was required for sustenance and expression of the Th1 effector/memory response to mycobacterial Ags...
  19. pmc Pharmacological blockade of CCR1 ameliorates murine arthritis and alters cytokine networks in vivo
    M Amat
    Department of Biology, Drug Discovery, Almirall Research Center, Sant Feliu de Llobregat, Barcelona, Spain
    Br J Pharmacol 149:666-75. 2006
    ..To explore the impact of CCR1 blockade in experimental arthritis and the underlying mechanisms, we used J-113863, a non-peptide antagonist of the mouse receptor...
  20. ncbi CCR4 is a key modulator of innate immune responses
    Traci L Ness
    Department of Pathology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA
    J Immunol 177:7531-9. 2006
    ..These data stress the importance of CCR4 in macrophage differentiation and innate immune responses to pathogens, as well as the involvement of chemokine receptor expression in TLR signaling regulation...
  21. ncbi The chemokine receptor CCR6 is an important component of the innate immune response
    Haitao Wen
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
    Eur J Immunol 37:2487-98. 2007
    ..These data illustrate that CCR6 deficiency alters the innate response via attenuating the hyperactive local and systemic inflammatory response during CLP-induced peritonitis...
  22. ncbi TLR9 activation is a key event for the maintenance of a mycobacterial antigen-elicited pulmonary granulomatous response
    Toshihiro Ito
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    Eur J Immunol 37:2847-55. 2007
    ..These results suggest that TLR9 plays an important role in maintaining the appropriate phenotype in a Th1 granulomatous response...
  23. ncbi The chemokine CCL6 promotes innate immunity via immune cell activation and recruitment
    Ana L Coelho
    Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Immunol 179:5474-82. 2007
    ..Thus, CCL6 attenuates the immune failure during sepsis, in part, through a protective type 1-cytokine mediated mechanism...
  24. ncbi Dendritic cells at the interface of innate and acquired immunity: the role for epigenetic changes
    Haitao Wen
    University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109 2200, USA
    J Leukoc Biol 83:439-46. 2008
    ....
  25. pmc Epigenetic regulation of dendritic cell-derived interleukin-12 facilitates immunosuppression after a severe innate immune response
    Haitao Wen
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    Blood 111:1797-804. 2008
    ..These data implicate histone modification enzymes in suppressing DC-derived IL-12, which may provide one of the mechanisms of long-term immunosuppression subsequent to the septic response...
  26. pmc Toll-like receptors, Notch ligands, and cytokines drive the chronicity of lung inflammation
    Tracy Raymond
    Immunology Program and Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109 2200, USA
    Proc Am Thorac Soc 4:635-41. 2007
    ....
  27. pmc TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events
    Karen A Cavassani
    Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
    J Exp Med 205:2609-21. 2008
    ..Collectively, these data show that TLR3 is a regulator of the amplification of immune response and serves an endogenous sensor of necrosis, independent of viral activation...
  28. pmc TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4
    Toshihiro Ito
    Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 2200, USA
    J Clin Invest 119:33-46. 2009
    ..Furthermore, TLR9 seems to be required for optimal dll4 expression and the regulation of Mycobacterium antigen-elicited granuloma formation in mice...
  29. pmc Lung contusion: inflammatory mechanisms and interaction with other injuries
    Krishnan Raghavendran
    Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA
    Shock 32:122-30. 2009
    ....
  30. pmc Toll-like receptor 9 activation is a key mechanism for the maintenance of chronic lung inflammation
    Toshihiro Ito
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Am J Respir Crit Care Med 180:1227-38. 2009
    ..Accumulating evidence supports the hypothesis that the continuous host response to a persistent challenge can polarize the cytokine environment toward a Th2 cytokine phenotype, but the mechanisms responsible for this skewing are not clear...
  31. pmc Cytokine induced phenotypic and epigenetic signatures are key to establishing specific macrophage phenotypes
    Nicolai A Kittan
    Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
    PLoS ONE 8:e78045. 2013
    ..In addition, we describe a novel role for MLL as marker for classical activation. Our findings provide new insights into MΦ polarization that could be helpful to distinguish MΦ activation states...

Research Grants30

  1. Suppression of T cell immunity during sepsis
    Thomas S Griffith; Fiscal Year: 2013
    ....