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

Abstract

IL-17A is a T cell-specific cytokine that is involved in chronic inflammations, such as Mycobacterium infection, Crohn's disease, rheumatoid arthritis and multiple sclerosis. Mouse models have explained the molecular basis of IL-17A production and have shown that IL-17A has a positive effect not only on granuloma formation and neurodegeneration through unknown mechanisms, but also on bone resorption through Receptor activator of NF-kappaB ligand (RANKL) induction in osteoblasts. 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. 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 LCH and observed in IL-17A-related diseases. 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.

Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

“…IL-17A induces the production of proinfl ammatory mediators, metalloproteases, and antimicrobial peptides ( 15 ). We also demonstrated that IL-17A promotes long-term survival of monocyte-derived DCs and their fusion into multinucleated giant cells ( 16,17 ). In vitro, the short DC life span was extended above 12 days by exposure of DCs to IL-17A, suggesting that IL-17A-treated DCs may contribute to the development of chronic infl ammation resulting from multiple DC-T-cell cross talks, in vivo.…”

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…However, naive T cells from patients suffering from hyper-IgE syndrome lost the potential to differentiate into Th17 cells [12]. In human donors suffering from Langerhans cell (LC) histiocytosis, IL-17A was found in skin LC, CD3/CD28-activated T cells, and monocyte-derived DC (MoDC), but not in MoDC from healthy donors [13]. Murine OVA-pulsed CD4 1 T cells secreted IL-17A after stimulation with skin-derived DC [14].…”

Lung Diseases - Selected State of the Art Reviews

“…E.g. Wegener granulomatosis (Abdulahad et al 2008), Langerhans histiocytosis (Coury et al 2008), and hypersensitivity pneumonitis (Joshi et al 2009;Simonian et al 2009) have been reported to be linked to IL-17. Pulmonary IL-17 producing γδ T cells have also been detected in response to bleomycin-induced tissue damage, a model for induced pulmonary fibrosis (Braun et al 2010).…”