Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice

J Clin Invest. 2011 Jun;121(6):2264-77. doi: 10.1172/JCI43157. Epub 2011 May 16.


Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are 2 similar diseases characterized by a cytokine storm, overwhelming inflammation, multiorgan dysfunction, and death. Animal models of HLH suggest that disease is driven by IFN-γ produced by CD8⁺ lymphocytes stimulated by persistent antigen exposure. In these models and patients with "primary" HLH, the antigen persists due to genetic defects, resulting in ineffective cytotoxic responses by CD8⁺ T cells and poor pathogen clearance. However, infectious triggers are often not identified in patients with MAS, and some patients with HLH or MAS lack defects in cytotoxic T cell killing. Herein, we show that repeated stimulation of TLR9 produced an HLH/MAS-like syndrome on a normal genetic background, without exogenous antigen. Like previous HLH models, TLR9-induced MAS was IFN-γ dependent; however, unlike other models, disease did not require lymphocytes. We further showed that IL-10 played a protective role in this model and that blocking IL-10 signaling led to the development of hemophagocytosis. IL-10 may therefore be an important target for the development of effective therapeutics for MAS. Our data provide insight into MAS-like syndromes in patients with inflammatory diseases in which there is chronic innate immune activation but no genetic defects in cytotoxic cell function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CpG Islands / immunology
  • Cytokines / metabolism
  • DNA-Binding Proteins / drug effects
  • Disease Models, Animal
  • Immunity, Innate
  • Interferon-gamma / deficiency
  • Interferon-gamma / physiology*
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin-10 / antagonists & inhibitors
  • Interleukin-10 / physiology
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation
  • Lymphohistiocytosis, Hemophagocytic / physiopathology
  • Macrophage Activation Syndrome / etiology*
  • Macrophage Activation Syndrome / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Immunological
  • NK Cell Lectin-Like Receptor Subfamily B / antagonists & inhibitors
  • NK Cell Lectin-Like Receptor Subfamily B / immunology
  • Radiation Chimera
  • Systemic Inflammatory Response Syndrome / physiopathology
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / deficiency
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / physiology*


  • Antigens, Ly
  • Cytokines
  • DNA-Binding Proteins
  • IL10 protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • Klrb1c protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily B
  • Rag2 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Interleukin-10
  • Interferon-gamma