Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice
Edward M. Behrens, … , Taku Kambayashi, Gary A. Koretzky
Edward M. Behrens, … , Taku Kambayashi, Gary A. Koretzky
Published May 16, 2011
Citation Information: J Clin Invest. 2011;121(6):2264-2277. https://doi.org/10.1172/JCI43157.
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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 8

IL-10 receptor blockade results in a more severe MAS-like phenotype with the presence of hemophagocytosis.

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IL-10 receptor blockade results in a more severe MAS-like phenotype with...
(A) Serum IL-10 (dotted line) and IFN-γ (solid line) levels were measured by ELISA over the course of repeated CpG injections. (B) Serum IL-10 levels were measured by ELISA at day 10 of repeated CpG injection in wild-type, Ifng–/–, and Rag2–/– mice. (C–F) Mice were given repeated CpG or PBS injections according to the same schedule as in Figure 1. Mice were given concurrent injections of isotype or anti–IL-10R antibody with each dose. (C) Daily weights were measured, (D) complete blood count was performed on day 5, and (E) splenic weight and (F) serum ferritin were measured at sacrifice at day 6, when most mice receiving anti–IL-10R treatment became moribund. (G) Livers taken at sacrifice on day 6 were stained by H&E. Representative sections are shown at an original magnification of ×100. (H) Splenic touch preparations were made at sacrifice on day 6, and peripheral blood smears made at the time of complete blood count on day 5 were stained by Wright-Giemsa and evaluated for hemophagocytosis. Representative fields (original magnification, ×1,000 fields) are shown for mice receiving both CpG and anti–IL-10R antibody. All results are representative of 3–4 experiments. Individual symbols each represent 1 mouse, with the horizontal lines representing the mean values.