Targeting interferon-γ in hyperinflammation: opportunities and challenges

Fabrizio De Benedetti, Giusi Prencipe, Claudia Bracaglia, Emiliano Marasco, Alexei A Grom

Research output: Contribution to journalReview articlepeer-review


Interferon-γ (IFNγ) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFNγ underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFNγ in hyperinflammatory diseases, such as primary haemophagocytic lymphohistiocytosis, various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome, and cytokine release syndrome, all of which are often managed by rheumatologists or in consultation with rheumatologists. Given the effects of IFNγ on B cells and T follicular helper cells, a role for IFNγ in systemic lupus erythematosus pathogenesis is emerging. To improve our understanding of the role of IFNγ in human disease, IFNγ-related biomarkers that are relevant for the management of hyperinflammatory diseases are progressively being identified and studied, especially because circulating levels of IFNγ do not always reflect its overproduction in tissue. These biomarkers include STAT1 (specifically the phosphorylated form), neopterin and the chemokine CXCL9. IFNγ-neutralizing agents have shown efficacy in the treatment of primary haemophagocytic lymphohistiocytosis in clinical trials and initial promising results have been obtained in various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome. In clinical practice, there is a growing body of evidence supporting the usefulness of circulating CXCL9 levels as a biomarker reflecting IFNγ production.

Original languageEnglish
Pages (from-to)678-691
Number of pages14
JournalNat. Rev. Rheumatol.
Issue number11
Publication statusPublished - Nov 2021


  • Animals
  • Antibodies, Monoclonal, Humanized/immunology
  • Biomarkers/blood
  • Chemokine CXCL9/blood
  • Crohn Disease/blood
  • Disease Models, Animal
  • Humans
  • Immune System Diseases/blood
  • Immunity/immunology
  • Inflammation/blood
  • Interferon-gamma/antagonists & inhibitors
  • Lymphohistiocytosis, Hemophagocytic/blood
  • Macrophage Activation Syndrome/blood
  • Mice
  • Neopterin/blood
  • STAT1 Transcription Factor/blood


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