Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice
Edward M. Behrens, Scott W. Canna, Katharine Slade, Sheila Rao, Portia A. Kreiger, Michele Paessler, Taku Kambayashi, Gary A. Koretzky
Edward M. Behrens, Scott W. Canna, Katharine Slade, Sheila Rao, Portia A. Kreiger, Michele Paessler, Taku Kambayashi, Gary A. Koretzky
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Research Article Immunology

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

Edward M. Behrens, Scott W. Canna, Katharine Slade, Sheila Rao, Portia A. Kreiger, Michele Paessler, Taku Kambayashi, Gary A. Koretzky

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Figure 7

Simultaneous deletion of NK cells and lymphocytes partially reduces the severity of CpG-induced HLH/MAS-like syndrome, whereas cDCs are required for early-phase IFN-γ production but are dispensable for disease.

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Simultaneous deletion of NK cells and lymphocytes partially reduces the ...
(A–C) Rag2–/– and Rag2–/–Il2rg–/– mice were treated with repeated PBS or CpG injections as in Figure 1. (A) Peripheral blood counts were assessed at day 8, and spleen size was assessed at day 10. (B) Liver inflammation, assessed at day 10, was quantitated as in Figure 2. (C) Serum IFN-γ levels were also assessed at day 10. Data are representative of 2 experiments. (D–G) CD11c-DTR marrow was injected into lethally irradiated wild-type mice that were then allowed to rest for 8 weeks. These mice were then injected on alternating days with DT (100 ng) and either CpG or PBS as in Figure 1. (D) IFN-γ levels were measured by ELISA on day 1 and day 10. (E) Peripheral blood counts were assessed at day 8, and (F) spleen size was assessed at day 10. (G) Liver inflammation, assessed at day 10, was quantitated as in Figure 2. Individual symbols each represent 1 mouse, with the horizontal lines representing the mean values.