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1.
J Clin Invest ; 131(18)2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34343136

RESUMO

IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Interleucina-1beta/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Diferenciação Celular/imunologia , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/deficiência , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/imunologia , Ligante RANK/imunologia , Linfócitos T Reguladores/metabolismo
2.
Cells ; 10(7)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34359840

RESUMO

Osteosarcoma (OS) is a high-grade malignant stromal tumor composed of mesenchymal cells producing osteoid and immature bone, with a peak of incidence in the second decade of life. Hence, although relatively rare, the social impact of this neoplasm is particularly relevant. Differently from carcinomas, molecular genetics and the role of the tumor microenvironment in the development and progression of OS are mainly unknown. Indeed, while the tumor microenvironment has been widely studied in other solid tumor types and its contribution to tumor progression has been definitely established, tumor-stroma interaction in OS has been quite neglected for years. Only recently have new insights been gained, also thanks to the availability of new technologies and bioinformatics tools. A better understanding of the cross-talk between the bone microenvironment, including immune and stromal cells, and OS will be key not only for a deeper knowledge of osteosarcoma pathophysiology, but also for the development of novel therapeutic strategies. In this review, we summarize the current knowledge about the tumor microenvironment in OS, mainly focusing on immune cells, discussing their role and implication for disease prognosis and treatment response.


Assuntos
Neoplasias Ósseas/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Células-Tronco Mesenquimais/imunologia , Osteoclastos/imunologia , Osteossarcoma/imunologia , Macrófagos Associados a Tumor/imunologia , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Osso e Ossos/imunologia , Osso e Ossos/patologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Citocinas/genética , Citocinas/imunologia , Modelos Animais de Doenças , Humanos , Células-Tronco Mesenquimais/patologia , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Osteoclastos/patologia , Osteossarcoma/diagnóstico , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Prognóstico , Transdução de Sinais , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/patologia
3.
Front Immunol ; 12: 651049, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276648

RESUMO

Objective: Autoantibodies are detected in most patients with rheumatoid arthritis (RA) and can be of the IgM, IgG or IgA subclass. Correlations between IgA autoantibodies and more severe disease activity have been previously reported, but the functional role of IgA autoantibodies in the pathogenesis of RA is ill understood. In this study, we explored the effect of IgA immune complexes on osteoclast mediated bone resorption. Methods: Anti-citrullinated peptide antibody (ACPA) and anti-carbamylated protein (anti-CarP) antibody levels of the IgA and IgG isotype and rheumatoid factor (RF) IgA were determined in synovial fluid (SF) of RA patients. Monocytes, neutrophils, and osteoclasts were stimulated with precipitated immune complexes from SF of RA patients or IgA- and IgG-coated beads. Activation was determined by neutrophil extracellular trap (NET) release, cytokine secretion, and bone resorption. Results: NET formation by neutrophils was enhanced by SF immune complexes compared to immune complexes from healthy or RA serum. Monocytes stimulated with isolated SF immune complexes released IL-6 and IL-8, which correlated with the levels of ACPA IgA levels in SF. Osteoclasts cultured in the presence of supernatant of IgA-activated monocytes resorbed significantly more bone compared to osteoclasts that were cultured in supernatant of IgG-activated monocytes (p=0.0233). Osteoclasts expressed the Fc receptor for IgA (FcαRI; CD89) and Fc gamma receptors. IgA-activated osteoclasts however produced significantly increased levels of IL-6 (p<0.0001) and IL-8 (p=0.0007) compared to IgG-activated osteoclasts. Both IL-6 (p=0.03) and IL-8 (p=0.0054) significantly enhanced bone resorption by osteoclasts. Conclusion: IgA autoantibodies induce release of IL-6 and IL-8 by immune cells as well as osteoclasts, which enhances bone resorption by osteoclasts. We anticipate that this will result in more severe disease activity in RA patients. Targeting IgA-FcαRI interactions therefore represents a promising novel therapeutic strategy for RA patients with IgA autoantibodies.


Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Reabsorção Óssea/imunologia , Imunoglobulina A/imunologia , Osteoclastos/imunologia , Animais , Complexo Antígeno-Anticorpo/imunologia , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia , Reabsorção Óssea/sangue , Reabsorção Óssea/patologia , Bovinos , Armadilhas Extracelulares/metabolismo , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Articulação do Joelho/imunologia , Articulação do Joelho/patologia , Osteoclastos/metabolismo , Líquido Sinovial/imunologia
4.
Front Immunol ; 12: 688201, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248975

RESUMO

Bone erosion is one of the primary features of inflammatory arthritis and is caused by excessive differentiation and activation of osteoclasts. Fc gamma receptors (FcγRs) have been implicated in osteoclastogenesis. Our recent studies demonstrate that joint-deposited lupus IgG inhibited RANKL-induced osteoclastogenesis. FcγRI is required for RANKL-induced osteoclastogenesis and lupus IgG-induced signaling transduction. We reviewed the results of studies that analyzed the association between FcγRs and bone erosion in inflammatory arthritis. The analysis revealed the dual roles of FcγRs in bone destruction in inflammatory arthritis. Thus, IgG/FcγR signaling molecules may serve as potential therapeutic targets against bone erosion.


Assuntos
Artrite/metabolismo , Remodelação Óssea , Osso e Ossos/metabolismo , Osteoclastos/metabolismo , Osteogênese , Receptores de IgG/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Artrite/tratamento farmacológico , Artrite/imunologia , Artrite/patologia , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/imunologia , Osso e Ossos/patologia , Humanos , Imunoglobulina G/metabolismo , Imunoterapia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Receptores de IgG/antagonistas & inibidores , Receptores de IgG/imunologia , Transdução de Sinais
5.
Front Immunol ; 12: 691081, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34276682

RESUMO

Increasing evidence in recent years has suggested that regulatory B cells (Bregs) are one of the crucial modulators in various inflammatory disease conditions. However, no study to date has investigated the significance of Bregs in modulating osteoclastogenesis. To the best of our knowledge, in the present study, we for the first time examined the anti-osteoclastogenic potential of Bregs under in vitro conditions and observed that Bregs suppress RANKL-induced osteoclastogenesis in a dose-dependent manner. We further elucidated the mechanism behind the observed suppression of osteoclasts differentiation via Bregs. Our results clearly suggested that the observed anti-osteoclastogenic property of Bregs is mediated via the production of IL-10 cytokine. Next, we explored whether Bregs have any role in mediating inflammatory bone loss under post-menopausal osteoporotic conditions in ovx mice. Remarkably, our in vivo data clearly suggest that the frequencies of both CD19+IL-10+ Bregs and CD19+CD1dhiCD5+IL-10+ "B10" Bregs were significantly reduced in case of osteoporotic mice model. Moreover, we also found a significant reduction in serum IL-10 cytokine levels in osteoporotic mice, thereby further supporting our observations. Taken together, the present study for the first time establishes the direct role of regulatory B cells in modulating osteoclastogenesis in vitro. Further, our in vivo data suggest that modulations in the percentage of Bregs population along with its reduced potential to produce IL-10 might further exacerbate the observed bone loss in ovx mice.


Assuntos
Linfócitos B Reguladores/imunologia , Osteoporose Pós-Menopausa/imunologia , Animais , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-10/sangue , Interleucina-10/imunologia , Camundongos Endogâmicos C57BL , Osteoclastos/imunologia , Osteogênese , Osteoporose Pós-Menopausa/sangue , Ovariectomia , Baço/citologia
6.
Front Immunol ; 12: 657687, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079546

RESUMO

Peri-prosthetic osteolysis (PPO) and following aseptic loosening are regarded as the prime reasons for implant failure after joint replacement. Increasing evidence indicated that wear-debris-irritated inflammatory response and macrophage polarization state play essential roles in this osteolytic process. Harmine, a ß-carboline alkaloid primitively extracted from the Peganum harmala seeds, has been reported to have various pharmacological effects on monoamine oxidase action, insulin intake, vasodilatation and central nervous systems. However, the impact of harmine on debris-induced osteolysis has not been demonstrated, and whether harmine participates in regulating macrophage polarization and subsequent osteogenic differentiation in particle-irritated osteolysis remains unknown. In the present study, we investigated the effect of harmine on titanium (Ti) particle-induced osteolysis in vivo and in vitro. The results suggested harmine notably alleviated Ti particle-induced bone resorption in a murine PPO model. Harmine was also found to suppress the particle-induced inflammatory response and shift the polarization of macrophages from M1 phenotypes to M2 phenotypes in vivo and in vitro, which improved anti-inflammatory and bone-related cytokines levels. In the conditioned medium from Ti particle-stimulated murine macrophage RAW264.7 cells treated with harmine, the osteoblast differentiation ability of mouse pre-osteoblastic MC3T3-E1 cells was greatly increased. And we also provided evidences that the immunomodulatory capacity of harmine might be attributed to the inhibition of the c-Jun N-terminal kinase (JNK) in wear particle-treated macrophages. All the results strongly show that harmine might be a promising therapeutic agent to treat PPO.


Assuntos
Doenças Ósseas/etiologia , Doenças Ósseas/metabolismo , Harmina/farmacologia , Macrófagos/imunologia , Macrófagos/metabolismo , Osteogênese/efeitos dos fármacos , Titânio/efeitos adversos , Animais , Biomarcadores , Doenças Ósseas/diagnóstico , Doenças Ósseas/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Imunofluorescência , Imuno-Histoquímica , Inflamação/complicações , Inflamação/etiologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Masculino , Camundongos , Óxido Nítrico/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/metabolismo , Osteólise/diagnóstico , Osteólise/tratamento farmacológico , Osteólise/etiologia , Osteólise/metabolismo , Células RAW 264.7 , Microtomografia por Raio-X
7.
Clin Immunol ; 229: 108784, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34126239

RESUMO

OBJECTIVE: Osteoarthritis (OA), the leading cause of joint failure, is characterized by breakdown of articular cartilage and remodeling of subchondral bone in synovial joints. Despite the high prevalence and debilitating effects of OA, no disease-modifying drugs exist. Increasing evidence, including genetic variants of the interleukin 4 (IL-4) and IL-4 receptor genes, implicates a role for IL-4 in OA, however, the mechanism underlying IL-4 function in OA remains unknown. Here, we investigated the role of IL-4 in OA pathogenesis. METHODS: Il4-, myeloid-specific-Il4ra-, and Stat6-deficient and control mice were subjected to destabilization of the medial meniscus to induce OA. Macrophages, osteoclasts, and synovial explants were stimulated with IL-4 in vitro, and their function and expression profiles characterized. RESULTS: Mice lacking IL-4, IL-4Ra in myeloid cells, or STAT6 developed exacerbated cartilage damage and osteophyte formation relative to WT controls. In vitro analyses revealed that IL-4 downregulates osteoarthritis-associated genes, enhances macrophage phagocytosis of cartilage debris, and inhibits osteoclast differentiation and activation via the type I receptor. CONCLUSION: Our findings demonstrate that IL-4 protects against osteoarthritis in a myeloid and STAT6-dependent manner. Further, IL-4 can promote an immunomodulatory microenvironment in which joint-resident macrophages polarize towards an M2 phenotype and efficiently clear pro-inflammatory debris, and osteoclasts maintain a homeostatic level of activity in subchondral bone. These findings support a role for IL-4 modulation of myeloid cell types in maintenance of joint health and identify a pathway that could provide therapeutic benefit for osteoarthritis.


Assuntos
Interleucina-4/imunologia , Macrófagos/imunologia , Osteoartrite/prevenção & controle , Osteoclastos/imunologia , Animais , Cartilagem Articular/imunologia , Cartilagem Articular/patologia , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/prevenção & controle , Interleucina-4/deficiência , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoartrite/imunologia , Osteoartrite/patologia , Osteoclastos/patologia , Fagocitose , Receptores de Superfície Celular/deficiência , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Fator de Transcrição STAT6/deficiência , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais/imunologia
8.
Front Immunol ; 12: 636427, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897689

RESUMO

Macrophage activation and osteoclastogenesis are hallmarks of inflammatory osteolysis and may be targeted by the local application of liquid platelet-rich fibrin (PRF). Liquid PRF is produced by a hard spin of blood in the absence of clot activators and anticoagulants, thereby generating an upper platelet-poor plasma (PPP) layer, a cell-rich buffy coat layer (BC; termed concentrated-PRF or C-PRF), and the remaining red clot (RC) layer. Heating PPP has been shown to generate an albumin gel (Alb-gel) that when mixed back with C-PRF generates Alb-PRF having extended working properties when implanted in vivo. Evidence has demonstrated that traditional solid PRF holds a potent anti-inflammatory capacity and reduces osteoclastogenesis. Whether liquid PRF is capable of also suppressing an inflammatory response and the formation of osteoclasts remains open. In the present study, RAW 264.7 and primary macrophages were exposed to lipopolysaccharides (LPS), lactoferrin, and agonists of Toll-like receptors (TLR3 and TLR7) in the presence or absence of lysates prepared by freeze-thawing of liquid PPP, BC, Alb-gel, and RC. For osteoclastogenesis, primary macrophages were exposed to receptor activator of nuclear factor kappa B ligand (RANKL), macrophage colony-stimulating factor (M-CSF), and human transforming growth factor-ß1 (TGF-ß1) in the presence or absence of PPP, BC, Alb-gel, RC lysates and hemoglobin. We show here that it is mainly the lysates prepared from PPP and BC that consistently reduced the agonist-induced expression of interleukin 6 (IL6) and cyclooxygenase-2 (COX2) in macrophages, as determined by RT-PCR and immunoassay. With respect to osteoclastogenesis, lysates from PPP and BC but also from RC, similar to hemoglobin, reduced the expression of osteoclast marker genes tartrate-resistant acid phosphatase (TRAP) and cathepsin K, as well as TRAP histochemical staining. These findings suggest that liquid PRF holds a potent in vitro heat-sensitive anti-inflammatory activity in macrophages that goes along with an inhibition of osteoclastogenesis.


Assuntos
Inflamação/prevenção & controle , Ativação de Macrófagos , Macrófagos/metabolismo , Osteoclastos/metabolismo , Osteogênese , Plasma Rico em Plaquetas/metabolismo , Animais , Imiquimode/farmacologia , Inflamação/sangue , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Lactoferrina/farmacologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/metabolismo , Camundongos , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteogênese/efeitos dos fármacos , Fenótipo , Poli I-C/farmacologia , Células RAW 264.7 , Receptor 3 Toll-Like/agonistas , Receptor 3 Toll-Like/metabolismo , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/metabolismo
9.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805598

RESUMO

Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following formation of a micrometastatic tumour mass by inhibiting metastatic processes including angiogenesis, bone remodeling and immunosuppressive cell functions. In this review we will highlight some of the mechanisms mediating DTC dormancy and the complex relationships which occur between tumor cells and bone resident cells in the bone metastatic microenvironment. These inter-cellular interactions may be important targets to consider for development of novel effective therapies for the prevention or treatment of bone metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/prevenção & controle , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/prevenção & controle , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/patologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/imunologia , Osso e Ossos/patologia , Comunicação Celular , Citocinas/genética , Citocinas/metabolismo , Humanos , Metástase Linfática , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/imunologia , Osteoblastos/patologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/patologia , Transdução de Sinais , Evasão Tumoral/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores de Crescimento do Endotélio Vascular/genética , Fatores de Crescimento do Endotélio Vascular/metabolismo
10.
Curr Allergy Asthma Rep ; 21(4): 23, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33768371

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to recognize clinical features of Paget's disease of bone and to describe how the osteoclast, a myeloid-derived cell responsible for bone resorption, contributes to the disease. RECENT FINDINGS: Recent studies have identified several variants in SQSTM1, OPTN, and other genes that may predispose individuals to Paget's disease of bone; studies of these genes and their protein products have elucidated new roles for these proteins in bone physiology. Understanding the pathologic mechanisms in the Pagetic osteoclast may lead to the identification of future treatment targets for other inflammatory and autoimmune diseases characterized by abnormal bone erosion and/or osteoclast activation.


Assuntos
Remodelação Óssea , Osteíte Deformante , Osteoclastos , Algoritmos , Remodelação Óssea/efeitos dos fármacos , Remodelação Óssea/genética , Remodelação Óssea/imunologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/imunologia , Osso e Ossos/patologia , Humanos , Osteíte Deformante/diagnóstico , Osteíte Deformante/etiologia , Osteíte Deformante/fisiopatologia , Osteíte Deformante/terapia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/patologia
11.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670600

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints. Inflammation, new blood vessel formation (angiogenesis) and bone resorption (osteoclastogenesis) are three key processes involved in the joint damage and deformities of arthritis. Various gut microbiota-derived metabolites are implicated in RA pathogenesis. However, there is barely any information about the impact of two such metabolites, indole-3-aldehyde (IAld) and indole-3-acetic acid (I3AA), on arthritis-related processes. We conducted a comparative analysis of IAld and I3AA using established cell-based models to understand how they might influence RA pathogenesis. Although structurally similar, the bioactivities of these two metabolites were profoundly different. IAld but not I3AA, inhibited the expression of pro-inflammatory cytokines (IL-1ß and IL-6) in RAW 264.7 (RAW) cells stimulated with heat-killed M. tuberculosis sonicate (Mtb) and lipopolysaccharide (LPS). IAld also exhibited pro-angiogenic activity and pro-osteoclastogenic activity. In contrast, I3AA exhibited anti-angiogenic activity on endothelial cell tube formation but had no effect on osteoclastogenesis. Both IAld and I3AA have been proposed as aryl hydrocarbon receptor (AhR) agonists. Use of CH-223191, an inhibitor of the AhR, suppressed the anti-angiogenic activity of I3AA but failed to mitigate the effects of IAld. Further investigation of the anti-inflammatory activities of IAld and I3AA in LPS-treated RAW cells indicated that inhibition of MyD88-dependent activation of NF-κB and MAPK pathways was not likely involved. Our results suggest that the relative bioavailability of these indole derivatives may differentially impact RA progression and possibly other diseases that share similar cellular processes.


Assuntos
Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Citocinas/imunologia , Ácidos Indolacéticos/imunologia , Indóis/imunologia , Microbiota/imunologia , Animais , Artrite Reumatoide/metabolismo , Doenças Autoimunes/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Temperatura Alta , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacologia , Indóis/metabolismo , Indóis/farmacologia , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/imunologia , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Células RAW 264.7
12.
Arthritis Rheumatol ; 73(7): 1145-1154, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33512089

RESUMO

OBJECTIVE: We have previously reported that stimulation of mouse bone marrow-derived macrophages with tumor necrosis factor (TNF) and interleukin-6 (IL-6) induces differentiation of osteoclast-like cells. We undertook this study to clarify the characterization and function of human TNF and IL-6-induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors. METHODS: Peripheral blood monocytes were cultured with a combination of TNF and IL-6, TNF alone, IL-6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL-6-induced osteoclasts or RANKL-induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole-body bone mineral density (BMD) was examined. RESULTS: Peripheral blood monocytes stimulated with a TNF and IL-6-induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL-6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL-6-induced osteoclast formation. Expression levels of IL1ß, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL-6-induced osteoclasts, but not in RANKL-induced osteoclasts. The number of TNF and IL-6-induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL-induced osteoclast numbers negatively correlated with the whole-body BMD of the same patients. CONCLUSION: Our results demonstrate that TNF and IL-6-induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA.


Assuntos
Artrite Reumatoide/imunologia , Reabsorção Óssea/imunologia , Interleucina-6/imunologia , Osteoclastos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Idoso , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/metabolismo , Densidade Óssea , Reabsorção Óssea/diagnóstico por imagem , Reabsorção Óssea/metabolismo , Estudos de Casos e Controles , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Subunidade p40 da Interleucina-12/efeitos dos fármacos , Subunidade p40 da Interleucina-12/imunologia , Subunidade p40 da Interleucina-12/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/farmacologia , Masculino , Metaloproteinase 3 da Matriz/efeitos dos fármacos , Metaloproteinase 3 da Matriz/imunologia , Metaloproteinase 3 da Matriz/metabolismo , Pessoa de Meia-Idade , Fatores de Transcrição NFATC/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/imunologia , Ligante RANK/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
13.
Eur J Immunol ; 51(3): 714-720, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33079387

RESUMO

Thirty percent of psoriasis patients develop psoriatic arthritis (PsA), nevertheless the mechanism remains unknown. Endogenous GU-rich miRNAs activate endosomal TLR7 that plays a critical role in autoimmune diseases. We found that endogenous TLR7 ligands, miR-29 and miR-Let7b, were markedly increased in PsA compared to osteoarthritis (OA) synovial fluid (SF)s. We showed that intradermal (i.d.) miR-Let7b injection promoted skin inflammation, which was characterized by amplified Th1 cells, CD68+ M1 macrophages, and transcriptional upregulation of glycolytic mediators, GLUT1, C-MYC, and HIF1α. Expansion of skin Th1 cells driven by miR-Let7b was also linked to elevated M1-associated IRFs. Interestingly, i.d. miR-Let7b administration exacerbated suboptimal joint inflammation along with metabolic reconfiguration of the PsA-like preclinical model. Moreover, TLR7 agonist, R837, potentiated metabolic reprogramming and expression of IL-1ß, IL-6, and IL-12 in murine macrophages, enabling myeloid-to-T-cell crosstalk. Consistently, treatment with glycolytic inhibitors, 2-DG and/or HIF1αi, reversed R837-induced metabolic remodeling and disrupted the TLR7-driven inflammatory phenotype in myeloid and lymphoid cells. Similar to miR-Let7b, R837 also differentiates progenitor cells into mature osteoclasts, primarily through RANKL induction. Taken together, this study indicates that TLR7-instigated metabolic rewiring of macrophages and their cross-regulation of T cells connects skin immunopathology to joint inflammation.


Assuntos
Artrite Psoriásica/imunologia , Articulações/imunologia , Macrófagos/imunologia , Pele/imunologia , Receptor 7 Toll-Like/imunologia , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Citocinas/imunologia , Humanos , Inflamação/imunologia , Ligantes , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos DBA , MicroRNAs/imunologia , Células Mieloides/imunologia , Osteoclastos/imunologia , Transdução de Sinais/imunologia , Líquido Sinovial/imunologia , Células Th1/imunologia
14.
Rheumatology (Oxford) ; 60(5): 2409-2420, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33246326

RESUMO

OBJECTIVES: While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. METHODS: We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. RESULTS: Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. CONCLUSION: Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.


Assuntos
Artrite Reumatoide/imunologia , Reabsorção Óssea/imunologia , Monócitos/imunologia , Células Supressoras Mieloides/imunologia , Osteoclastos/imunologia , Células Th17/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Reabsorção Óssea/patologia , Diferenciação Celular/imunologia , Humanos , Camundongos , Fenótipo
15.
Eur J Immunol ; 51(4): 903-914, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33347617

RESUMO

This study elucidates the mechanism of CCL25 and CCR9 in rheumatoid arthritis (RA). RA synovial fluid (SF) expresses elevated levels of CCL25 compared to OA SF and plasma from RA and normal. CCL25 was released into RA SF by fibroblasts (FLS) and macrophages (MΦs) stimulated with IL-1ß and IL-6. CCR9 is also presented on IL-1ß and IL-6 activated RA FLS and differentiated MΦs. Conversely, in RA PBMCs neither CCL25 nor CCR9 are impacted by 3-month longitudinal TNF inhibitor therapy. CCL25 amplifies RA FLS and monocyte infiltration via p38 and ERK phosphorylation. CCL25-stimulated RA FLS secrete potentiated levels of IL-8 which is disrupted by p38 and ERK inhibitors. CCL25 polarizes RA monocytes into nontraditional M1 MΦs that produce IL-8 and CCL2. Activation of p38 and ERK cascades are also responsible for the CCL25-induced M1 MΦ development. Unexpectedly, CCL25 was unable to polarize RA PBMCs into effector Th1/Th17 cells. Consistently, lymphokine like RANKL was uninvolved in CCL25-induced osteoclastogenesis; however, this manifestation was regulated by osteoclastic factors such as RANK, cathepsin K (CTSK), and TNF-α. In short, we reveal that CCL25/CCR9 manipulates RA FLS and MΦ migration and inflammatory phenotype in addition to osteoclast formation via p38 and ERK activation.


Assuntos
Artrite Reumatoide/imunologia , Diferenciação Celular/imunologia , Quimiocinas CC/imunologia , Macrófagos/imunologia , Osteoclastos/imunologia , Receptores CCR/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Células Cultivadas , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Quimiocinas CC/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/citologia , Fibroblastos/imunologia , Fibroblastos/metabolismo , Humanos , Interleucina-8/imunologia , Interleucina-8/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Fosforilação , Receptores CCR/metabolismo , Transdução de Sinais/imunologia , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
16.
J Leukoc Biol ; 108(4): 1037-1050, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33311847

RESUMO

Bone destruction in inflammatory osteolytic diseases including periodontitis is related to excessive activity of osteoclasts (OC), which originate from precursor cells of the myeloid lineage, termed osteoclast precursors (OCP). In contrast to ample knowledge that we currently have on mature OC, little is known about OCP and their regulation during bacterial infection. Therefore, this study aimed to identify and characterize OCP following chronic infection with a periodontal bacteria Porphyromonas gingivalis (Pg). We used a micro-osmotic pump to continually release Pg subcutaneously in a murine model. Two weeks after Pg infection, the frequency of CD11b+c-fms+Ly6Chi population is significantly elevated within the bone marrow, spleen and peripheral blood. In vitro and in vivo studies identified these cells as the OCP-containing population and Pg infection significantly enhanced the osteoclastogenic activity of these cells. Furthermore, mRNA sequencing analysis indicated a unique gene and pathway profile in CD11b+c-fms+Ly6Chi population following Pg infection, with changes in genes and pathways related to OC differentiation, cell proliferation and apoptosis, inflammatory response, phagocytosis and immunity, as well as antigen processing and presentation. Moreover, using IL-6 knockout mice, we found that IL-6 is important for Pg-induced accumulation of CD11b+c-fms+Ly6Chi population from the bone marrow and periphery. Our results provide new insights into the characterization and regulation of OCP following a chronic bacterial infection. This knowledge is relevant to the understanding of the pathogenesis of bacteria-induced bone loss, and to the identification of potential therapeutic targets of bone loss diseases.


Assuntos
Infecções por Bacteroidaceae/imunologia , Diferenciação Celular/imunologia , Osteoclastos/imunologia , Osteólise/imunologia , Porphyromonas gingivalis/imunologia , Células-Tronco/imunologia , Animais , Infecções por Bacteroidaceae/genética , Infecções por Bacteroidaceae/patologia , Diferenciação Celular/genética , Doença Crônica , Modelos Animais de Doenças , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Camundongos Knockout , Osteoclastos/patologia , Osteólise/genética , Osteólise/microbiologia , Osteólise/patologia , Células-Tronco/patologia
17.
Sci Rep ; 10(1): 20363, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33230147

RESUMO

Osteoclasts (OCs) and much less dendritic cells (DCs) induce significant expansion and functional activation of NK cells, and furthermore, the OC-expanded NK cells preferentially increase the expansion and activation of CD8+ T cells by targeting CD4+ T cells. When autologous OCs were used to expand patient NK cells much lower percentages of expanded CD8+ T cells, decreased numbers of expanded NK cells and decreased functions of NK cells could be observed, and the addition of allogeneic healthy OCs increased the patients' NK function. Mechanistically, OC-expanded NK cells were found to lyse CD4+ T cells but not CD8+ T cells suggesting potential selection of CD8+ T cells before their expansion by OC activated NK cells. In agreement, Increased IFN-γ secretion, and NK cell-mediated cytotoxicity and higher percentages of CD8+ T cells, in various tissue compartments of oral tumor-bearing hu-BLT mice in response to immunotherapy by OC-expanded NK cells were observed. Thus, our results indicate an important relationship between NK and CD8+ T cells.


Assuntos
Carcinoma de Células Escamosas/terapia , Citotoxicidade Imunológica , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias Bucais/terapia , Osteoclastos/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Comunicação Celular/imunologia , Proliferação de Células , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/patologia , Humanos , Imunofenotipagem , Interferon gama/biossíntese , Interferon gama/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/transplante , Ativação Linfocitária , Contagem de Linfócitos , Camundongos , Camundongos Transgênicos , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Osteoclastos/patologia , Cultura Primária de Células , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Immunol ; 205(10): 2595-2605, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33020147

RESUMO

Siglec-15 is a conserved sialic acid-binding Ig-like lectin, which is expressed on osteoclasts. Deficiency of Siglec-15 leads to an impaired osteoclast development, resulting in a mild osteopetrotic phenotype. The role of Siglec-15 in arthritis is still largely unclear. To address this, we generated Siglec-15 knockout mice and analyzed them in a mouse arthritis model. We could show that Siglec-15 is directly involved in pathologic bone erosion in the K/BxN serum-transfer arthritis model. Histological analyses of joint destruction provided evidence for a significant reduction in bone erosion area and osteoclast numbers in Siglec-15-/- mice, whereas the inflammation area and cartilage destruction was comparable to wild-type mice. Thus, Siglec-15 on osteoclasts has a crucial function for bone erosion during arthritis. In addition, we generated a new monoclonal anti-Siglec-15 Ab to clarify its expression pattern on immune cells. Whereas this Ab demonstrated an almost exclusive Siglec-15 expression on murine osteoclasts and hardly any other expression on various other immune cell types, human Siglec-15 was more broadly expressed on human myeloid cells, including human osteoclasts. Taken together, our findings show a role of Siglec-15 as a regulator of pathologic bone resorption in arthritis and highlight its potential as a target for future therapies, as Siglec-15 blocking Abs are available.


Assuntos
Artrite Reumatoide/imunologia , Reabsorção Óssea/imunologia , Imunoglobulinas/metabolismo , Proteínas de Membrana/metabolismo , Osteoclastos/metabolismo , Animais , Artrite Experimental/sangue , Artrite Experimental/complicações , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Reumatoide/sangue , Artrite Reumatoide/complicações , Artrite Reumatoide/genética , Reabsorção Óssea/patologia , Osso e Ossos/imunologia , Osso e Ossos/patologia , Células Cultivadas , Feminino , Humanos , Imunoglobulinas/genética , Leucócitos Mononucleares , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Osteoclastos/imunologia , Cultura Primária de Células
19.
Biosci Trends ; 14(5): 342-348, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-32908076

RESUMO

The human immune system has evolved to recognize and eradicate pathogens, a process that is known as "host defense". If, however, the immune system does not work properly, it can mistakenly attack the body's own tissues and induce autoimmune diseases. Rheumatoid arthritis (RA) is such an autoimmune disease in which the synovial joints are predominately attacked by the immune system. Moreover, RA is associated with bone destruction and joint deformity. Although biologic agents have propelled RA treatment forward dramatically over the past 30 years, a considerable number of patients with RA still experience progressive bone damage and joint disability. That is to be expected since current RA therapies are all intended to halt inflammation but not to alleviate bone destruction. A better understanding of bone erosions is crucial to developing a novel strategy to treat RA-associated erosions. This review provides insights into RA-associated bone destruction and perspectives for future clinical interventions.


Assuntos
Artrite Reumatoide/complicações , Fatores Biológicos/farmacologia , Conservadores da Densidade Óssea/farmacologia , Osteoporose/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Fatores Biológicos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Caderinas/farmacologia , Caderinas/uso terapêutico , Humanos , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Cápsula Articular/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/imunologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteogênese/efeitos dos fármacos , Osteogênese/imunologia , Osteoporose/tratamento farmacológico , Osteoporose/patologia , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Ligante RANK/antagonistas & inibidores , Ligante RANK/imunologia , Ligante RANK/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/imunologia
20.
FASEB J ; 34(11): 15327-15337, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32951236

RESUMO

Palatal expansion has been widely used for the treatment of transverse discrepancy or maxillae hypoplasia, but the biological mechanism of bone formation during this procedure is largely unknown. Osteoclasts, which could be regulated by T cells and other components of the immune system, play a crucial role in force-induced bone remodeling. However, whether T cells participate in the palatal expansion process remains to be determined. In this study, we conducted the tooth borne rapid palatal expansion model on the mouse, and detect whether the helper T cells (Th) and regulatory T cells (Treg) could affect osteoclasts and further bone formation. After bonding open spring palatal expanders for 3-day, 5-day, 7-day, and retention for 28-day, micro-computed tomography scanning, histologic, and immunofluorescence staining were conducted to evaluate how osteoclasts were regulated by T cells during the bone remodeling process. We revealed that the increased osteoclast number was downregulated at the end of the early stage of rapid palatal expansion. Type 1 helper T (Th1) cells and Type 17 helper T (Th17) cells increased initially and promoted osteoclastogenesis. Thereafter, the regulatory T (Treg) cells emerged and maintained a relatively high level at the late stage of the experiment to downregulate the osteoclast number by inhibiting Th1 and Th17 cells, which governed the new bone formation. In conclusion, orchestrated T cells are able to regulate osteoclasts at the early stage of rapid palatal expansion and further facilitate bone formation during retention. This study identifies that T cells participate in the palatal expansion procedure by regulating osteoclasts and implies the potential possibility for clinically modulating T cells to improve the palatal expansion efficacy.


Assuntos
Remodelação Óssea , Osteoclastos/citologia , Osteogênese , Palato/citologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/imunologia , Técnica de Expansão Palatina , Palato/imunologia
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