Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome

Giusi Prencipe, Ivan Caiello, Antonia Pascarella, Alexei A. Grom, Claudia Bracaglia, Laurence Chatel, Walter G. Ferlin, Emiliano Marasco, Raffaele Strippoli, Cristina de Min, Fabrizio De Benedetti

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Abstract

Background: The pathogenesis of macrophage activation syndrome (MAS) is not clearly understood: a large body of evidence supports the involvement of mechanisms similar to those implicated in the setting of primary hemophagocytic lymphohistiocytosis. Objective: We sought to investigate the pathogenic role of IFN-γ and the therapeutic efficacy of IFN-γ neutralization in an animal model of MAS. Methods: We used an MAS model established in mice transgenic for human IL-6 (IL-6TG mice) challenged with LPS (MAS mice). Levels of IFN-γ and IFN-γ-inducible chemokines were evaluated by using real-time PCR in the liver and spleen and by means of ELISA in plasma. IFN-γ neutralization was achieved by using the anti-IFN-γ antibody XMG1.2 in vivo. Results: Mice with MAS showed a significant upregulation of the IFN-γ pathway, as demonstrated by increased mRNA levels of Ifng and higher levels of phospho-signal transducer and activator of transcription 1 in the liver and spleen and increased expression of the IFN-γ-inducible chemokines Cxcl9 and Cxcl10 in the liver and spleen, as well as in plasma. A marked increase in Il12a and Il12b expression was also found in livers and spleens of mice with MAS. In addition, mice with MAS had a significant increase in numbers of liver CD68+ macrophages. Mice with MAS treated with an anti-IFN-γ antibody showed a significant improvement in survival and body weight recovery associated with a significant amelioration of ferritin, fibrinogen, and alanine aminotransferase levels. In mice with MAS, treatment with the anti-IFN-γ antibody significantly decreased circulating levels of CXCL9, CXCL10, and downstream proinflammatory cytokines. The decrease in CXCL9 and CXCL10 levels paralleled the decrease in serum levels of proinflammatory cytokines and ferritin. Conclusion: These results provide evidence for a pathogenic role of IFN-γ in the setting of MAS.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
DOIs
Publication statusAccepted/In press - Jan 1 2017

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Keywords

  • Hemophagocytic lymphohistiocytosis
  • IFN-γ
  • Macrophage activation syndrome

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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