Abstract
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*
Substances
-
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