Immature dendritic cells in multiple myeloma are prone to osteoclast‐like differentiation through interleukin‐17A stimulation

Abstract

SummaryInterleukin 17A (IL17A), a cytokine involved in allergy, inflammation and osteoclastogenesis, was investigated in multiple myeloma (MM) to assess its role in the osteoclast (OC)-like activity of marrow immature dendritic cells (iDCs). Comparing nine MM patients with control subjects affected by monoclonal gammopathy of undetermined significance, we found high IL17A expression in the marrow plasma of MM patients in parallel with its deposits within the stromal matrix. Increased expression of the IL17A receptor (IL17RA) was also found in primary myeloma iDCs, which underwent OC-like transdifferentiation after IL17A stimulation. To assess the role of IL17A, we measured the activity of the IL17/IL17RA pathway in IL17A-transdifferentiated iDCs and the expression of functional OC genes by Western blotting and real-time polymerase chain reaction. These cells showed increased RNA transcription of genes enrolled in the maturation of OCs, while NFATC1 and FOS were induced by IL17A, independently of NFKB1 phosphorylation. Moreover, the concurrent phosphorylation of the Lip isoform of CEBPB and the down-regulation of MAFB supported the activation of IL17RA pathway in OC-like transdifferentiated iDCs that was apparently unrelated to TNFRSF11A signalling. These data emphasize the involvement of iDCs in MM hyperactive osteoclastogenesis and suggest that their bone resorption activity is also regulated, at least in vitro, by IL17RA.

Non-redundant roles for Th17 and Th22 cells in multiple myeloma clinical correlates

“…In addition to the correlation with the extent of bone disease, 17 it has been recently reported that primary immature dendritic cells in MM are prone to osteoclast-like trans-differentiation after IL-17 stimulation. 24 Other roles have been ascribed to IL-17, such as promotion of MM cell growth/survival, which is supported by the expression of the IL-17 receptor on MM cell lines and primary tumors, 15,25 and inhibition of immune cell functions. 15 However, no direct correlation between Th17 cell numbers and disease prognosis and/or severity has been provided.…”

Alternative pathways of osteoclastogenesis in inflammatory arthritis

“…21 Similarly, in multiple myeloma, IL-17A stimulates immature DCs to differentiate into osteoclast-like cells. 22 Evidence to date suggests that maturation of DCs might attenuate their differentiation into osteoclasts, but this area requires further investigation. 23 DCs are a heterogeneous cell lineage that includes various subtypes, such as CD11c + CD4 + cells, CD11c + CD8 + cells and CD11c + CD4 − CD8 − cells, and it remains to be determined whether a unique subset of immature DCs function as osteoclast precursors.…”

New Insights Into the Molecular Pathogenesis of Langerhans Cell Histiocytosis

“…However, given that IL-17A targeting drugs are still only in preclinical development for applications in LCH [85], the precise function of this cytokine in the disease needs to be elucidated to define the molecular pathways involved in the osteoclast-like transdifferentiation of dendritic cells. This phenomenon has been well established in other malignancies; we ourselves reported it in multiple myeloma, in which it is dependent on the activation of the receptor activator for nuclear factor kB (RANK)/RANKL, CD47/thrombospondin-1, and, overall, IL-17A/IL-17A receptor axes [86][87][88]. However, definite evidence in LCH is still lacking.…”