Selective regulation of macrophage activation

Summary

Principal Investigator: Xiaoyu Hu
Abstract: DESCRIPTION (provided by applicant): Classically activated or inflammatory macrophages are characterized by enhanced microbial killing, production of inflammatory cytokines such as TNF, IL-1 and IL-6, and high level production of IL-6/IL-12 family cytokines (IL-6, IL-12, IL-23 and IL-27) that regulate acquired immune responses. Inflammatory macrophages and their cytokine products play a key role in the pathogenesis of many autoimmune/inflammatory diseases, including rheumatoid arthritis (RA), inflammatory bowel disease and atherosclerosis, and possibly systemic lupus erythematosus (SLE). This application will focus on mechanisms that selectively regulate expression of specific subsets of inflammatory macrophage genes. Selective regulation of subsets of macrophage genes allows fine-tuning of distinct effector functions. Our long term goals are to understand mechanisms that selectively regulate macrophage effector functions important in human autoimmune and inflammatory diseases and to utilize this knowledge in development of new therapeutic approaches. We are particularly interested in regulation of activation and function of human monocytes as they enter inflammatory sites and differentiate into inflammatory macrophages, as this activation process is highly relevant for inflammatory disease pathogenesis. Therefore, we have initiated studies to identify mechanisms that selectively regulate human monocyte/macrophage activation in response to the prototypic macrophage-activating receptors TLR4 and TLR2. These TLRs elicit strong macrophage activation that serves as a good model for studying macrophage responses to inflammatory factors, including cytokines such as IL-1 and TNF that activate similar pathways. In addition, TLRs have been directly implicated in many autoimmune diseases, likely secondary to mediating responses to damaged tissues or cells (for example TLR2/4 in arthritis and TLR3/7/8/9 in lupus). We have identified a specific subset of TLR-inducible genes that are synergistically activated by TLRs and the Notch signaling pathway. Notch pathway components and target genes are expressed during inflammation, including in arthritis and atherosclerosis. TLRs directly activated Notch- dependent genes by IKK- and p38-mediated pathways, including activation of the transcriptional repressors Hes1 and Hey1 that selectively regulated expression of IL-6, IL-12 and IL-27. In this application, we will investigate molecular mechanisms by which TLRs and Notch synergize to activate expression of macrophage effector genes and the mechanisms and (patho)physiological significance of cytokine gene regulation by Hes1 and Hey1. We will use human systems that are directly relevant for inflammatory disease pathogenesis and murine models to further address the in vivo significance of our findings. We anticipate that our studies will yield insights into selective regulation of macrophage effector functions that can be exploited for therapeutic interventions to suppress inflammation in autoimmune diseases. PUBLIC HEALTH RELEVANCE: Macrophages are immune cells that produce inflammatory cytokines that are important in many autoimmune and inflammatory diseases, including rheumatoid arthritis (RA), inflammatory bowel disease and atherosclerosis, and possibly systemic lupus erythematosus (SLE). Cytokines are proven therapeutic targets in human autoimmune diseases, and this application will focus on understanding how the production of these cytokines is regulated. We anticipate that our studies will yield insights that can be exploited for therapeutic interventions to suppress inflammation in autoimmune diseases.
Funding Period: 2010-02-01 - 2014-12-31
more information: NIH RePORT

Top Publications

  1. pmc Autoamplification of Notch signaling in macrophages by TLR-induced and RBP-J-dependent induction of Jagged1
    Julia Foldi
    Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, Hospital for Special Surgery, New York, NY 10021, USA
    J Immunol 185:5023-31. 2010
  2. pmc Notch- and transducin-like enhancer of split (TLE)-dependent histone deacetylation explain interleukin 12 (IL-12) p70 inhibition by zymosan
    Yolanda Alvarez
    Instituto de Biologia y Genetica Molecular, Consejo Superior de Investigaciones Cientificas, 47003 Valladolid, Spain
    J Biol Chem 286:16583-95. 2011
  3. pmc Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages
    Sung Ho Park
    Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA
    Nat Immunol 12:607-15. 2011
  4. pmc Myxoma virus induces type I interferon production in murine plasmacytoid dendritic cells via a TLR9/MyD88-, IRF5/IRF7-, and IFNAR-dependent pathway
    Peihong Dai
    Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    J Virol 85:10814-25. 2011
  5. pmc TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J
    Baohong Zhao
    Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10065, USA
    J Exp Med 209:319-34. 2012
  6. pmc Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization
    Haixia Xu
    Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA
    Nat Immunol 13:642-50. 2012
  7. pmc Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2
    Xuesong Qian
    Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St Louis, MO 63104, USA
    J Immunol 190:5894-902. 2013
  8. pmc Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling
    Yu Qiao
    Arthritis and Tissue Degeneration Program and Genomics Center, Hospital for Special Surgery, New York, NY 10021, USA
    Immunity 39:454-69. 2013

Detail Information

Publications8

  1. pmc Autoamplification of Notch signaling in macrophages by TLR-induced and RBP-J-dependent induction of Jagged1
    Julia Foldi
    Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, Hospital for Special Surgery, New York, NY 10021, USA
    J Immunol 185:5023-31. 2010
    ..Early and direct cooperation between TLR and Notch pathways leads to Jagged1-RBP-J-mediated autoamplification of Notch signaling that can modulate later phases of the TLR response...
  2. pmc Notch- and transducin-like enhancer of split (TLE)-dependent histone deacetylation explain interleukin 12 (IL-12) p70 inhibition by zymosan
    Yolanda Alvarez
    Instituto de Biologia y Genetica Molecular, Consejo Superior de Investigaciones Cientificas, 47003 Valladolid, Spain
    J Biol Chem 286:16583-95. 2011
    ....
  3. pmc Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages
    Sung Ho Park
    Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA
    Nat Immunol 12:607-15. 2011
    ..Our results demonstrate an unexpected homeostatic function for TNF and a GSK3-mediated mechanism for the prevention of prolonged and excessive inflammation...
  4. pmc Myxoma virus induces type I interferon production in murine plasmacytoid dendritic cells via a TLR9/MyD88-, IRF5/IRF7-, and IFNAR-dependent pathway
    Peihong Dai
    Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    J Virol 85:10814-25. 2011
    ....
  5. pmc TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J
    Baohong Zhao
    Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10065, USA
    J Exp Med 209:319-34. 2012
    ..These findings identify RBP-J as a key upstream negative regulator of osteoclastogenesis that restrains excessive bone resorption in inflammatory settings...
  6. pmc Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization
    Haixia Xu
    Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA
    Nat Immunol 13:642-50. 2012
    ....
  7. pmc Increased Th17 cells in the tumor microenvironment is mediated by IL-23 via tumor-secreted prostaglandin E2
    Xuesong Qian
    Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis University, St Louis, MO 63104, USA
    J Immunol 190:5894-902. 2013
    ..This inductive effect of PGE2 on IL-23 p19 transcription is mediated through cAMP/PKA signaling transduction pathway...
  8. pmc Synergistic activation of inflammatory cytokine genes by interferon-γ-induced chromatin remodeling and toll-like receptor signaling
    Yu Qiao
    Arthritis and Tissue Degeneration Program and Genomics Center, Hospital for Special Surgery, New York, NY 10021, USA
    Immunity 39:454-69. 2013
    ..Our results provide a synergy mechanism whereby IFN-γ creates a primed chromatin environment to augment TLR-induced gene transcription. ..

Research Grants30

  1. gp96, TLR and immunologic tolerance
    Zihai Li; Fiscal Year: 2013
    ....
  2. Activation of Macrophages in Human Autoimmune Diseases
    Lionel B Ivashkiv; Fiscal Year: 2013
    ..We anticipate that our studies will yield insights into regulation of cytokine production that can be exploited for therapeutic interventions to suppress autoimmunity and inflammation. ..
  3. Regulation of Type 1 Interferon Production by Autoimmunity-Associated PTPN22
    Yaya Wang; Fiscal Year: 2013
    ..In this grant I wil study the function of a genetic variant associated with multiple autoimmune diseases, the PTPN22 1858T variant, to examine its role in immune responses and disease pathogenesis. ..