Immune Interactions with CD4+ T Cells Promote the Development of Functional Osteoclasts from Murine CD11c+ Dendritic Cells

Abstract

Dendritic cells (DC) are innate immune effectors and are critically involved in regulating T cell immunity. Osteoclasts (OC) are bone-resorbing cells derived from the monocyte/macrophage lineage in response to receptor activator of NF-κB ligand (RANKL). DC and T cells form aggregates in the inflammatory infiltrates at active disease sites in human and in experimental rheumatoid arthritis and periodontitis. We investigated whether DC interactions with T cells in the bone environment can support the development of functional OC. In the present study, we demonstrate that upon proper activation by microbial or protein Ags (namely Actinobacillus actinomycetemcomitans, bovine insulin, and outer membrane protein-1) and during immune interactions with CD4+ T cells in vitro, murine BM-derived and splenic CD11c+ DC (CD11b−F4/80−Ly-6C−CD31−) develop into TRAP+CT-R+cathepsin-k+ functional OC in a RANKL/RANK-dependent manner. Rescue and blocking experiments using CD11c+ DC derived from Csf-1−/−op/op mice show that M-CSF is required “before” developing such osteoclastogenic potential upstream of RANKL/RANK signaling, suggesting that immature CD11c+ DC can indeed act like OC precursors. In addition, these CD11c+ DC-derived OC are capable of inducing bone loss after adoptive transfer in vivo. These data suggest a direct contribution of DC during immune interactions with CD4+ T cells to inflammation-induced osteoclastogenesis. Therefore, our findings not only provide further evidence for DC plasticity, but also extend the current paradigm of osteoimmunology.

Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis

“…Osteoclasts are formed by fusion of precursor cells of the monocyte/macrophage lineage, 60 and CD11c ϩ DCs contribute to the pool of osteoclasts. 44,61 Beyond the direct effects of myeloid cell products on osteoprogenitors, Th17 cells have also been incriminated in the dynamics of bone resorption. 33,59 Potentially relevant is the up-regulation of IL-7R expression in macrophages and DCs by P. gingivalis in light of recent evidence that IL-7 enhances osteoclastogenesis and directly sensitizes T cells to release pro-osteoclastogenic factors including TNF-␣ and RANKL.…”

The JNK-dependent CaMK pathway restrains the reversion of committed cells during osteoclast differentiation

“…Macrophages have the potential to differentiate to dendritic cells in the presence of GM-CSF and interleukin-4 (IL4) (Alnaeeli et al, 2006). We examined the response of pOCs treated with SP600125 in comparison with BMMs and vehicle-untreated pOCs when the cells were cultured in the presence of GM-CSF plus IL4.…”

“…To determine the phenotype of differentiated dendritic cells, cells were stained by FITClabeled anti-F4/80 and PE-Cy7-labeled anti-CD11c, and were subjected to cytometric analyses (Alnaeeli et al, 2006).…”

Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

“…In RA, the DCs are essential for initiation and perpetuation by Ag presentation as well as for cytokine and chemokine secretion (5,6). Furthermore, DCs are capable of transdifferentiating into osteoclasts, contributing directly to bone erosion (7,8). The maturation state of the DCs is crucial for determining the balance between tolerance and immunity.…”