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Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome.

  • Weiss, Eric S1
  • Girard-Guyonvarc'h, Charlotte2
  • Holzinger, Dirk3, 4
  • de Jesus, Adriana A5
  • Tariq, Zeshan6
  • Picarsic, Jennifer7
  • Schiffrin, Eduardo J8
  • Foell, Dirk3
  • Grom, Alexei A9
  • Ammann, Sandra10
  • Ehl, Stephan10
  • Hoshino, Tomoaki11
  • Goldbach-Mansky, Raphaela5
  • Gabay, Cem2
  • Canna, Scott W1
  • 1 RK Mellon Institute, Children's Hospital of Pittsburgh of UPMC/University of Pittsburgh, Pittsburgh, PA.
  • 2 Division of Rheumatology, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland. , (Switzerland)
  • 3 Department of Pediatric Rheumatology and Immunology, University Children's Hospital Muenster, Muenster, Germany. , (Germany)
  • 4 Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany. , (Germany)
  • 5 Translational Autoinflammatory Diseases Studies, National Institute of Allergy and Infectious Diseases, and.
  • 6 Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD.
  • 7 Department of Pathology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA.
  • 8 AB2Bio, Ltd., Lausanne, Switzerland. , (Switzerland)
  • 9 Pediatric Rheumatology, Cincinnati Children's Hospital, Cincinnati, OH.
  • 10 Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany; and. , (Germany)
  • 11 Division of Respirology, Neurology, and Rheumatology, Kurume University School of Medicine, Kurume, Japan. , (Japan)
Published Article
American Society of Hematology
Publication Date
Mar 29, 2018
DOI: 10.1182/blood-2017-12-820852
PMID: 29326099


Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ-induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.

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