IL-10 Critically Modulates B Cell Responsiveness in <i>Rankl−/−</i> Mice

Marrella, Veronica; Iacono, Nadia Lo; Fontana, Elena; Sobacchi, Cristina; Sic, Heiko; Schena, Francesca; Sereni, Lucia Piceni; Castiello, Maria Carmina; Poliani, Pietro Luigi; Vezzoni, Paolo; Cassani, Barbara; Traggiai, Elisabetta; Villa, Anna

doi:10.4049/jimmunol.1401977

Cited by 9 publications

(5 citation statements)

References 59 publications

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“…On the other hand, serum RANKL/OPG ratio was significantly decreased in Dpp3 KO mice (Fig. B ), possibly due to the contribution of other cell types to OPG levels in the circulation . Serological analysis revealed also a significant increase in TRAP and carboxyterminal collagen cross‐links (CTX) levels in Dpp3 KO mice, in line with enhanced bone resorption observed in the skeletal tissue, and a tendency to a reduction in parathyroid hormone (PTH), whereas no difference was found in serum total calcium and phosphate, procollagen type 1 N‐terminal propeptide (P1NP), and osteocalcin levels (Fig.…”

Section: Resultsmentioning

confidence: 77%

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

Menale

Robinson

Palagano

et al. 2019

Journal of Bone and Mineral Research

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Controlling oxidative stress through the activation of antioxidant pathways is crucial in bone homeostasis, and impairments of the cellular defense systems involved contribute to the pathogenesis of common skeletal diseases. In this work we focused on the dipeptidyl peptidase 3 (DPP3), a poorly investigated ubiquitous zinc‐dependent exopeptidase activating the Keap1‐Nrf2 antioxidant pathway. We showed Dpp3 expression in bone and, to understand its role in this compartment, we generated a Dpp3 knockout (KO) mouse model and specifically investigated the skeletal phenotype. Adult Dpp3 KO mice showed a mild growth defect, a significant increase in bone marrow cellularity, and bone loss mainly caused by increased osteoclast activity. Overall, in the mouse model, lack of DPP3 resulted in sustained oxidative stress and in alterations of bone microenvironment favoring the osteoclast compared to the osteoblast lineage. Accordingly, in vitro studies revealed that Dpp3 KO osteoclasts had an inherent increased resorptive activity and ROS production, which on the other hand made them prone to apoptosis. Moreover, absence of DPP3 augmented bone loss after estrogen withdrawal in female mice, further supporting its relevance in the framework of bone pathophysiology. Overall, we show a nonredundant role for DPP3 in the maintenance of bone homeostasis and propose that DPP3 might represent a possible new osteoimmunological player and a marker of human bone loss pathology. © 2019 American Society for Bone and Mineral Research.

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Section: Resultsmentioning

confidence: 77%

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

Menale

Robinson

Palagano

et al. 2019

Journal of Bone and Mineral Research

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“…Since its first recognition as a survival factor for dendritic cells allowing efficient T cells priming, a huge amount of data has been produced on the multiple functions of the RANKL cytokine in many different organ compartments, in physiopathological conditions . For what pertains to bone, studies have been “osteoclastocentric”; in fact, after the demonstration of the essential role played by RANKL in osteoclast differentiation and function, the investigations have mainly focused on alterations of osteoclast formation and activity in the presence of increased RANKL concentration or in its absence .…”

Section: Discussionmentioning

confidence: 99%

Murine Rankl−/− Mesenchymal Stromal Cells Display an Osteogenic Differentiation Defect Improved by a RANKL-Expressing Lentiviral Vector

Schena¹,

Menale

Caci

et al. 2017

Stem Cells

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Autosomal recessive osteopetrosis (ARO) is a severe bone disease characterized by increased bone density due to impairment in osteoclast resorptive function or differentiation. Hematopoietic stem cell transplantation is the only available treatment; however, this therapy is not effective in RANKL-dependent ARO, since in bone this gene is mainly expressed by cells of mesenchymal origin. Of note, whether lack of RANKL production might cause a defect also in the bone marrow (BM) stromal compartment, possibly contributing to the pathology, is unknown. To verify this possibility, we generated and characterized BM mesenchymal stromal cell (BM-MSC) lines from wild type and Rankl mice, and found that Rankl BM-MSCs displayed reduced clonogenicity and osteogenic capacity. The differentiation defect was significantly improved by lentiviral transduction of Rankl BM-MSCs with a vector stably expressing human soluble RANKL (hsRANKL). Expression of Rankl receptor, Rank, on the cytoplasmic membrane of BM-MSCs pointed to the existence of an autocrine loop possibly activated by the secreted cytokine. Based on the close resemblance of RANKL-defective osteopetrosis in humans and mice, we expect that our results are also relevant for RANKL-dependent ARO patients. Data obtained in vitro after transduction with a lentiviral vector expressing hsRANKL would suggest that restoration of RANKL production might not only rescue the defective osteoclastogenesis of this ARO form, but also improve a less obvious defect in the osteoblast lineage, thus possibly achieving higher benefit for the patients, when the approach is translated to clinics. Stem Cells 2017;35:1365-1377.

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“…This reveals that FcγRII low/− activated B cells represent a regulatory B-cell subset that has not been previously defined in human cancer tissues. More interestingly, IL-10 can act as an important regulator in promoting B-cell activation, proliferation, and maturation, although its suppressive role in limiting myeloid cell and T-cell functions has been established3637. It is plausible that IL-10 serving as a positive feedback during B-cell activation in cancer environments is utilized by tumours to suppress cytotoxic T-cell functions.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma

Ouyang

Yuan

et al. 2016

Nat Commun

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B cells are prominent components of human solid tumours, but activation status and functions of these cells in human cancers remain elusive. Here we establish that over 50% B cells in hepatocellular carcinoma (HCC) exhibit an FcγRIIlow/− activated phenotype, and high infiltration of these cells positively correlates with cancer progression. Environmental semimature dendritic cells, but not macrophages, can operate in a CD95L-dependent pathway to generate FcγRIIlow/− activated B cells. Early activation of monocytes in cancer environments is critical for the generation of semimature dendritic cells and subsequent FcγRIIlow/− activated B cells. More importantly, the activated FcγRIIlow/− B cells from HCC tumours, but not the resting FcγRIIhigh B cells, without external stimulation suppress autologous tumour-specific cytotoxic T-cell immunity via IL-10 signals. Collectively, generation of FcγRIIlow/− activated B cells may represent a mechanism by which the immune activation is linked to immune tolerance in the tumour milieu.

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IL-10 Critically Modulates B Cell Responsiveness in Rankl−/− Mice

Cited by 9 publications

References 59 publications

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

Absence of Dipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss

Murine Rankl−/− Mesenchymal Stromal Cells Display an Osteogenic Differentiation Defect Improved by a RANKL-Expressing Lentiviral Vector

Dendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma

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