title: Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice.
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.
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. behrens@email.chop.edu
authors.forename: Edward M
authors.initials: EM
authors.lastname: Behrens
authors.forename: Scott W
authors.initials: SW
authors.lastname: Canna
authors.forename: Katharine
authors.initials: K
authors.lastname: Slade
authors.forename: Sheila
authors.initials: S
authors.lastname: Rao
authors.forename: Portia A
authors.initials: PA
authors.lastname: Kreiger
authors.forename: Michele
authors.initials: M
authors.lastname: Paessler
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
authors.forename: Gary A
authors.initials: GA
authors.lastname: Koretzky
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects; D004195:Disease Models, Animal; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000172:deficiency / Q000502:physiology*; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051359:Lymphohistiocytosis, Hemophagocytic / Q000503:physiopathology; D055501:Macrophage Activation Syndrome / Q000209:etiology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000037:antagonists & inhibitors / Q000276:immunology; D011828:Radiation Chimera; D018746:Systemic Inflammatory Response Syndrome / Q000503:physiopathology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000950:Antigens, Ly; D016207:Cytokines; D004268:DNA-Binding Proteins; C556062:IL10 protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; C499308:Rag2 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D007371:Interferon-gamma