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

Publication date: Available online 12 August 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): 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
BackgroundThe 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 primary hemophagocytic lymphohistiocytosis.ObjectiveTo investigate the pathogenic role of interferon-γ (IFNγ) and the therapeutic efficacy of IFNγ neutralization in an animal model of macrophage activation syndrome.MethodsWe used a MAS model established in mice transgenic for human interleukin-6 (IL-6TG) challenged with LPS (MAS mice). Levels of IFNγ and IFNγ-inducible chemokines were evaluated by real-time PCR in liver and spleen and by ELISA in plasma. IFNγ neutralization was achieved using the anti-IFNγ antibody XMG1.2 in vivo.ResultsMAS mice showed a significant upregulation of the IFNγ pathway, as demonstrated by increased mRNA levels of Ifnγ and by higher levels of phospho-STAT1 in liver and spleen and by increased expression of IFNγ-inducible chemokines Cxcl9 and Cxcl10 in liver and spleen as well as in plasma. A marked increase in Il-12a and Il-12b expression was also found in liver and spleen from MAS mice. In addition, MAS mice showed a significant increase in liver CD68 positive macrophages. MAS mice treated with an anti-IFNγ antibody showed a significant improvement in survival and in body weight recovery, associated to a significant amelioration of ferritin, fibrinogen and alanine aminotransferase levels. In MAS mice, treatment with the anti-IFNγ antibody significantly decreased circulating levels of CXCL9, CXCL10 and downstream proinflammatory cytokines. The decrease in CXCL9 and CXCL10 levels paralleled the decrease in the serum levels of proinflammatory cytokines and ferritin.ConclusionThese results provide evidence for a pathogenic role of IFNγ in MAS.

Teaser

In a murine model of MAS, the IFNγ pathway is activated and has a pathogenic role, as neutralization of IFNγ reverts the disease. These results provide the rationale for the therapeutic targeting of IFNγ in MAS.


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