Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 15

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

  • Text
  • PDF
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

×

Figure 2

Repeatedly CpG-treated mice develop serologic and histologic features of cytokine storm.

Options: View larger image (or click on image) Download as PowerPoint
Repeatedly CpG-treated mice develop serologic and histologic features of...
Mice were treated with PBS and CpG as in Figure 1. (A) Serum levels of IFN-γ, IL-12, IL-10, and IL-6 were assessed by ELISA at day 10. (B–D) Hepatic inflammation was assessed at sacrifice on day 10 by a blinded pathologist using a standardized scoring system as follows: portal inflammation, 0, absent; 1, focal and minimal; 2, mild; 3, moderate; 4, marked; lobular inflammation, 0, absent; 1, rare small foci; 2, occasional small foci; 3, moderate small foci; 4, frequent small foci. (B) Livers were stained with H&E. Lobular infiltrates are marked with short arrows, and portal infiltrates are marked with long double arrows. Representative sections are shown at an original magnification of ×40. (C) Lobular and (D) portal inflammation were scored separately. (E) Hepatic infiltrates were stained by immunohistochemistry for T cell (CD3), B cell (B220), and macrophage (F4/80) markers. Representative sections are shown at an original magnification of ×200. (F) Splenic architecture was assessed by H&E stains of spleens on day 10 (original magnification, ×50 [left]; ×200 [right]). *P < 0.05 versus PBS for all experiments. Data are representative of 3 experiments. Individual symbols each represent 1 mouse, with the horizontal lines representing the mean values.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 8 X users
Referenced in 10 patents
On 1 Facebook pages
Highlighted by 1 platforms
181 readers on Mendeley
See more details