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.

Dendritic cells (DC) are the mononuclear cells that initiate adaptive immune responses.Osteoclasts (OC) are the multinucleated giant cells that resorb bone. As previously described for human conventional DC (cDC), we demonstrate that murine cDC, either in vitro generated from Fms-like tyrosine kinase 3 (Flt3) + bone marrow progenitors or ex vivo purified from spleen, are able to develop into OC in response to M-CSF and receptor activator of NF-jB ligand (RANKL) in vitro. This transdifferentiation is driven by the immune environment that controls cDC maturation, cell fusion, tartrate-resistant acid phosphatase (TRAP) and bone resorption activities. Only immature cDC have the capacity to become OC since mature cDC or plasmacytoid DC do not. Additions of the pro-inflammatory cytokines, such as IL-1b and TNF-a, or human rheumatoid synovial fluid, increase murine cDC transdifferentiation into OC, whereas IFN-a inhibits it. The adaptive cytokine, IFN-c, inhibits cDC fusion while IL-4 increases it. IL-2, IFN-c and IL-4 inhibit TRAP and bone resorption activities contrary to IL-10, which enhances both activities. A putative new "immune multinucleated giant cell" unable to resorb bone, which is formed owing to IL-4, is underlined. The future analysis of cDC transdifferentiation into OC in murine models of inflammatory arthritis will give us the quantitative importance of this phenomenon in vivo.

Dendritic cells (DCs), mononuclear cells that initiate immune responses, and osteoclasts (OCs), multinucleated bone-resorbing cells, are hematopoietic cells derived from monocytic precursor cells. Using in vitro generated dendritic cells, we previously showed that human and murine DCs could transdifferentiate into resorbing osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANKL). In this study we globally compared by transcriptomic profiling this new osteoclast differentiation pathway from DCs with the canonical differentiation pathway from monocytes. DNA chip data revealed that starting from two very distinct cell types, treatment with M-CSF and RANKL generated two highly similar types of osteoclast. In particular, DC-derived osteoclasts expressed all the characteristic marker genes of monocyte-derived osteoclasts. Two major molecular events could be observed during osteoclastogenesis: downregulation of a large set of monocyte or DC specific markers, together with upregulation of characteristic osteoclast marker genes. Most interestingly, our transcriptomic data showed a closer molecular profile between DCs and OCs than between monocytes and OCs. Our data establish DCs as a new osteoclast precursor able to generate OCs more efficiently than monocytes. ß

Langerhans cell histiocytosis (LCH) is a rare disease affecting people of any age, with widely variable clinical manifestations and different outcomes. The precise chain of events driving lesional granuloma formation has remained elusive for many years. There is evidence for inherited predisposition to and derangement of apoptosis and inflammation in lesional dendritic cells. Recently somatic BRAFV600E mutation in myeloid precursor dendritic cells was associated with the more aggressive form of the disease, although the same mutation in a more differentiated dendritic cell might drive a less aggressive disease. Whether this picture convincingly put LCH in the field of myeloid neoplasm remains to be determined. Altogether, these findings suggest that future therapeutic strategy might incorporate a screening of this genetic mutation for high-risk patients potentially suitable for target therapy.