Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion

Fabienne Coury, Nicola Annels, Aymeric Marie Christian Rivollier, Selma Olsson, Alessandra Santoro, Carole Speziani, Olga Azocar, Monique Flacher, Sophia Djebali, Jacques Tebib, Maria Brytting, R. Maarten Egeler, Chantal Rabourdin-Combe, Jan-Inge Henter, Maurizio Arico, Christine Servet-Delprat

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

IL-17A is a T cell-specific cytokine(1) that is involved in chronic inflammations, such as Mycobacterium infection(2), Crohn's disease(3), rheumatoid arthritis(4) and multiple sclerosis(5). Mouse models have explained the molecular basis of IL-17A production(6,7) and have shown that IL-17A has a positive effect not only on granuloma formation(8) and neurodegeneration(9) through unknown mechanisms, but also on bone resorption through Receptor activator of NF-kappa B ligand (RANKL) induction in osteoblasts(4,10). Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology, lacking an animal model, that cumulates symptoms that are found separately in various IL-17A-related diseases, such as aggressive chronic granuloma formation, bone resorption and soft tissue lesions with occasional neurodegeneration(11,12). We examined IL-17A in the context of LCH and found that there were high serum levels of IL-17A during active LCH and unexpected IL-17A synthesis by dendritic cells (DCs), the major cell type in LCH lesions. We also found an IL-17A-dependent pathway for DC fusion, which was highly potentiated by IFN-gamma and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN-gamma expression has been previously documented in LCH13 and observed in IL-17A-related diseases(14-17). Notably, serum IL-17A-dependent fusion activity correlates with LCH activity. Thus, IL-17A and IL-17A-stimulated DCs represent targets that may have clinical value in the treatment of LCH and other IL-17A-related inflammatory disorders.
Original languageEnglish
JournalNature Medicine
Volume14
Issue number1
Pages (from-to)81-87
ISSN1078-8956
DOIs
Publication statusPublished - 2008
Externally publishedYes

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