Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 583
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS Pathog ; 15(4): e1007744, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30978245

RESUMO

Staphylococcus aureus is able to infect virtually all organ systems and is a frequently isolated etiologic agent of osteomyelitis, a common and debilitating invasive infection of bone. Treatment of osteomyelitis requires invasive surgical procedures and prolonged antibiotic therapy, yet is frequently unsuccessful due to extensive pathogen-induced bone damage that can limit antibiotic penetration and immune cell influx to the infectious focus. We previously established that S. aureus triggers profound alterations in bone remodeling in a murine model of osteomyelitis, in part through the production of osteolytic toxins. However, staphylococcal strains lacking osteolytic toxins still incite significant bone destruction, suggesting that host immune responses are also major drivers of pathologic bone remodeling during osteomyelitis. The objective of this study was to identify host immune pathways that contribute to antibacterial immunity during S. aureus osteomyelitis, and to define how these immune responses alter bone homeostasis and contribute to bone destruction. We specifically focused on the interleukin-1 receptor (IL-1R) and downstream adapter protein MyD88 given the prominent role of this signaling pathway in both antibacterial immunity and osteo-immunologic crosstalk. We discovered that while IL-1R signaling is necessary for local control of bacterial replication during osteomyelitis, it also contributes to bone loss during infection. Mechanistically, we demonstrate that S. aureus enhances osteoclastogenesis of myeloid precursors in vitro, and increases the abundance of osteoclasts residing on bone surfaces in vivo. This enhanced osteoclast abundance translates to trabecular bone loss, and is dependent on intact IL-1R signaling. Collectively, these data define IL-1R signaling as a critical component of the host response to S. aureus osteomyelitis, but also demonstrate that IL-1R-dependent immune responses trigger collateral bone damage through activation of osteoclast-mediated bone resorption.


Assuntos
Reabsorção Óssea/imunologia , Fator 88 de Diferenciação Mieloide/fisiologia , Osteoclastos/imunologia , Osteomielite/imunologia , Receptores Tipo I de Interleucina-1/fisiologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Reabsorção Óssea/metabolismo , Reabsorção Óssea/microbiologia , Diferenciação Celular , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoclastos/metabolismo , Osteoclastos/microbiologia , Osteomielite/metabolismo , Osteomielite/microbiologia , Transdução de Sinais , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia
2.
Biomed Res Int ; 2019: 9042542, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30719451

RESUMO

This study aimed to explore periodontal and systemic immune response of overweight hosts to periodontitis. Forty C57 BL/6J male mice were divided into high (HF) or low fat (LF) diet groups and fed with the two diets, respectively, for 8 weeks. Each diet group was then divided into periodontitis (P) or control (C) groups (n = 10 per group) for 10-day ligation or sham-ligation. Overweight-related parameters including body weight were measured. Alveolar bone loss (ABL) was morphometrically analyzed and periodontal osteoclasts were stained. Periodontal immune response including leukocyte and macrophage number and inflammatory cytokines were analyzed by histology and quantitative PCR. Serum cytokine and lipid levels were quantified using electrochemiluminescence immunoassays, enzyme-linked immunosorbent assays, and biochemistry. It was found that HF group had 14.4% body weight gain compared with LF group (P < 0.01). ABL and periodontal osteoclast, leukocyte, and macrophage number were higher in P group than C group regardless of diet (P < 0.05). ABL and periodontal osteoclast number were not affected by diet regardless of ligation or sham-ligation. Leukocyte and macrophage number and protein level of tumor necrosis factor α (TNF-α) in periodontium and serum interleukin-6 level were downregulated by HF diet in periodontitis mice (P < 0.05). Periodontal protein level of TNF-α was highly correlated with serum interleukin-6 and low-density lipoprotein cholesterol levels (P < 0.01). These findings indicated that impaired immune response occurs both periodontally and systemically in preobesity overweight individuals. Given a well-reported exacerbating effect of obesity on periodontitis, overweight, if let uncontrolled, might place the individuals at potential risk for future periodontal tissue damage.


Assuntos
Sobrepeso/imunologia , Periodontite/imunologia , Periodonto/imunologia , Perda do Osso Alveolar/sangue , Perda do Osso Alveolar/imunologia , Animais , Peso Corporal/imunologia , Citocinas/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Leucócitos/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/imunologia , Osteoclastos/imunologia , Sobrepeso/sangue , Bolsa Periodontal/sangue , Bolsa Periodontal/imunologia , Periodontite/sangue , Roedores , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
3.
Am J Pathol ; 189(2): 370-390, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30660331

RESUMO

Commensal gut microbiota-host immune responses are experimentally delineated via gnotobiotic animal models or alternatively by antibiotic perturbation of gut microbiota. Osteoimmunology investigations in germ-free mice, revealing that gut microbiota immunomodulatory actions critically regulate physiologic skeletal development, highlight that antibiotic perturbation of gut microbiota may dysregulate normal osteoimmunological processes. We investigated the impact of antibiotic disruption of gut microbiota on osteoimmune response effects in postpubertal skeletal development. Sex-matched C57BL/6T mice were administered broad-spectrum antibiotics or vehicle-control from the age of 6 to 12 weeks. Antibiotic alterations in gut bacterial composition and skeletal morphology were sex dependent. Antibiotics did not influence osteoblastogenesis or endochondral bone formation, but notably enhanced osteoclastogenesis. Unchanged Tnf or Ccl3 expression in marrow and elevated tumor necrosis factor-α and chemokine (C-C motif) ligand 3 in serum indicated that the pro-osteoclastic effects of the antibiotics are driven by increased systemic inflammation. Antibiotic-induced broad changes in adaptive and innate immune cells in mesenteric lymph nodes and spleen demonstrated that the perturbation of gut microbiota drives a state of dysbiotic hyperimmune response at secondary lymphoid tissues draining local gut and systemic circulation. Antibiotics up-regulated the myeloid-derived suppressor cells, immature myeloid progenitor cells known for immunosuppressive properties in pathophysiologic inflammatory conditions. Myeloid-derived suppressor cell-mediated immunosuppression can be antigen specific. Therefore, antibiotic-induced broad suppression of major histocompatibility complex class II antigen presentation genes in bone marrow discerns that antibiotic perturbation of gut microbiota dysregulates critical osteoimmune cross talk.


Assuntos
Antibacterianos/efeitos adversos , Microbioma Gastrointestinal , Osteogênese , Maturidade Sexual , Animais , Antibacterianos/farmacologia , Quimiocina CCL3/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Linfonodos/imunologia , Linfonodos/patologia , Masculino , Mesentério/imunologia , Mesentério/patologia , Camundongos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteogênese/imunologia , Maturidade Sexual/efeitos dos fármacos , Maturidade Sexual/imunologia , Baço/imunologia , Baço/patologia , Fator de Necrose Tumoral alfa/imunologia
4.
Am J Pathol ; 189(1): 147-161, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30339839

RESUMO

The terminal complement complex (TCC) is formed on activation of the complement system, a crucial arm of innate immunity. TCC formation on cell membranes results in a transmembrane pore leading to cell lysis. In addition, sublytic TCC concentrations can modulate various cellular functions. TCC-induced effects may play a role in the pathomechanisms of inflammatory disorders of the bone, including rheumatoid arthritis and osteoarthritis. In this study, we investigated the effect of the TCC on bone turnover and repair. Mice deficient for complement component 6 (C6), an essential component for TCC assembly, and mice with a knockout of CD59, which is a negative regulator of TCC formation, were used in this study. The bone phenotype was analyzed in vivo, and bone cell behavior was analyzed ex vivo. In addition, the mice were subjected to a femur osteotomy. Under homeostatic conditions, C6-deficient mice displayed a reduced bone mass, mainly because of increased osteoclast activity. After femur fracture, the inflammatory response was altered and bone formation was disturbed, which negatively affected the healing outcome. By contrast, CD59-knockout mice only displayed minor skeletal alterations and uneventful bone healing, although the early inflammatory reaction to femur fracture was marginally enhanced. These results demonstrate that TCC-mediated effects regulate bone turnover and promote an adequate response to fracture, contributing to an uneventful healing outcome.


Assuntos
Regeneração Óssea , Complexo de Ataque à Membrana do Sistema Complemento , Fraturas do Fêmur , Consolidação da Fratura , Osteoclastos , Animais , Regeneração Óssea/genética , Regeneração Óssea/imunologia , Antígenos CD59/deficiência , Técnicas de Cultura de Células , Complemento C6/deficiência , Complexo de Ataque à Membrana do Sistema Complemento/genética , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Eritrócitos/imunologia , Eritrócitos/metabolismo , Eritrócitos/patologia , Fraturas do Fêmur/genética , Fraturas do Fêmur/imunologia , Fraturas do Fêmur/metabolismo , Fraturas do Fêmur/patologia , Consolidação da Fratura/genética , Consolidação da Fratura/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Knockout , Osteoclastos/imunologia , Osteoclastos/metabolismo , Osteoclastos/patologia , Ovinos
5.
Immunol Lett ; 205: 65-70, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29702149

RESUMO

The relationship between bone and immune cells is well established both in physiological and pathological conditions. Multiple myeloma (MM) is a plasma cell malignancy characterized by an increase of number and activity of osteoclasts (OCLs) and a decrease of osteoblasts (OBs). These events are responsible for bone lesions of MM patients. OCLs support MM cells survival in vitro and in vivo. Recently, the possible role of OCLs as immunosuppressive cells in the MM BM microenvironment has been underlined. OCLs protect MM cells against T cell-mediated cytotoxicity through the expression of several molecules including programmed death-ligand (PD-L) 1, galectin (Gal) 9, CD200, and indoleamine-2,3-dioxygenase (IDO). Among the molecules that could be involved in the link between immune-microenvironment and osteoclastogenesis the role of CD38 has been hypothesized. CD38 is a well-known adhesion molecule and an ectoenzyme highly expressed by MM cells. Moreover, CD38 is expressed by OCLs and at the surface level on OCL precursors. Targeting CD38 with monoclonal antibodies showed inhibition of both osteoclastogenesis and OCL-mediated suppression of T cell function. This review elucidates this evidence indicating that osteoclastogenesis affect MM immune-microenvironment being a potential target to improve anti-MM immunity and to ameliorate bone disease.


Assuntos
ADP-Ribosil Ciclase 1/imunologia , Glicoproteínas de Membrana/imunologia , Mieloma Múltiplo/patologia , Osteoclastos/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , ADP-Ribosil Ciclase 1/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Humanos , Imunomodulação/efeitos dos fármacos , Glicoproteínas de Membrana/metabolismo , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
6.
Leukemia ; 33(2): 426-438, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30135465

RESUMO

We investigate here how APRIL impacts immune regulatory T cells and directly contributes to the immunosuppressive multiple myeloma (MM) bone marrow (BM) microenvironment. First, APRIL receptor TACI expression is significantly higher in regulatory T cells (Tregs) than conventional T cells (Tcons) from the same patient, confirmed by upregulated Treg markers, i.e., Foxp3, CTLA-4. APRIL significantly stimulates proliferation and survival of Tregs, whereas neutralizing anti-APRIL monoclonal antibodies (mAbs) inhibit these effects. Besides TACI-dependent induction of cell cycle progression and anti-apoptosis genes, APRIL specifically augments Foxp3, IL-10, TGFß1, and PD-L1 in Tregs to further enhance Treg-inhibited Tcon proliferation. APRIL further increases MM cell-driven Treg (iTreg) via TACI-dependent proliferation associated with upregulated IL-10, TGFß1, and CD15s in iTreg, which further inhibits Tcons. Osteoclasts producing APRIL and PD-L1 significantly block Tcon expansion by iTreg generation, which is overcome by combined treatment with anti-APRIL and anti-PD1/PD-L1 mAbs. Finally, APRIL increases IL-10-producing B regulatory cells (Bregs) via TACI on BM Bregs of MM patients. Taken together, these results define novel APRIL actions via TACI on Tregs and Bregs to promote MM cell survival, providing the rationale for targeting APRIL/TACI system to alleviate the immunosuppressive BM milieu and improve patient outcome in MM.


Assuntos
Tolerância Imunológica/imunologia , Imunossupressão , Mieloma Múltiplo/imunologia , Osteoclastos/imunologia , Linfócitos T Reguladores/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Anticorpos Monoclonais/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Humanos , Imunossupressores/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Transdução de Sinais , Proteína Transmembrana Ativadora e Interagente do CAML/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
7.
Front Immunol ; 9: 2226, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319661

RESUMO

This review describes the IL-20 family of cytokines in rheumatoid arthritis (RA) and spondyloartrhitits (SpA) including psoriatic arthritis. The IL-20 receptor (R) cytokines IL-19, IL-20, and IL-24 are produced in both the peripheral blood and the synovial joint and are induced by Toll-like receptor ligands and autoantibody-associated immune complexes in monocytes. IL-19 seems to have anti-inflammatory functions in arthritis. In contrast, IL-20 and IL-24 increase the production of proinflammatory molecules such as monocyte chemoattractant protein 1 and are associated with bone degradation and radiographic progression. IL-22 is also associated with progression of bone erosions. This suggests that the IL-22RA1 subunit shared by IL-20, IL-22, and IL-24 is important for bone homeostasis. In line with this, the IL-22RA1 has been found on preosteoclasts in early RA. IL-26 is produced in high amounts by myofibroblasts and IL-26 stimulation of monocytes is an important inducer of Th17 cells in RA. This indicates a role for IL-26 as an important factor in the interactions between resident synovial cells and infiltrating leukocytes. Clinical trials that investigate inhibitors of IL-20 (fletikumab) and IL-22 (fezakinumab) in psoriasis and RA have been terminated. Instead, it seems that the strategy for modulating the IL-20 cytokine family should take the overlap in cellular sources and effector mechanisms into account. The redundancy encourages inhibition of more than one cytokine or one of the shared receptors. All IL-20 family members utilize the Janus kinase signaling pathway and are therefore potentially inhibited by drugs targeting these enzymes. Effects and adverse effects in ongoing clinical trials with inhibitors of IL-22 and the IL-22RA1 subunit and recombinant IL-22 fusion proteins will possibly provide important information about the IL-20 subfamily of cytokines in the future.


Assuntos
Artrite Psoriásica/imunologia , Artrite Reumatoide/imunologia , Receptores de Interleucina/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes/farmacologia , Anticorpos Neutralizantes/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Interleucinas/metabolismo , Janus Quinases/imunologia , Janus Quinases/metabolismo , Osteoclastos/imunologia , Osteoclastos/metabolismo , Receptores de Interleucina/antagonistas & inibidores , Receptores de Interleucina/metabolismo , Transdução de Sinais/imunologia , Membrana Sinovial/citologia , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Resultado do Tratamento
8.
J Dent Res ; 97(13): 1416-1423, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30205018

RESUMO

Sex is a biological variable that affects immune responses to bacterial and other types of infectious agents. Males and females are known to have differential oral bacterial disease burden in periodontal and endodontic disease. Understanding that there is a contribution from both sex and gender to these oral diseases, we discuss in this review recent sex-based findings that provide a pathobiological basis for differences observed between males and females. Sexual dimorphism of immune responses with respect to neutrophil trafficking and osteoclast differentiation and formation is presented as a plausible mechanism to explain the sexual differences. We also emphasize that sex, as a biological variable, should be considered in these types of oral immunologic studies.


Assuntos
Infecções Bacterianas/imunologia , Neutrófilos/imunologia , Osteoclastos/imunologia , Doenças Periodontais/imunologia , Caracteres Sexuais , Infecções Bacterianas/microbiologia , Quimiocinas/imunologia , Feminino , Humanos , Masculino , Doenças Periodontais/microbiologia
9.
J Cell Mol Med ; 22(12): 6002-6014, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30247799

RESUMO

The anaphylatoxin C5a is generated upon activation of the complement system, a crucial arm of innate immunity. C5a mediates proinflammatory actions via the C5a receptor C5aR1 and thereby promotes host defence, but also modulates tissue homeostasis. There is evidence that the C5a/C5aR1 axis is critically involved both in physiological bone turnover and in inflammatory conditions affecting bone, including osteoarthritis, periodontitis, and bone fractures. C5a induces the migration and secretion of proinflammatory cytokines of osteoblasts. However, the underlying mechanisms remain elusive. Therefore, in this study we aimed to determine C5a-mediated downstream signalling in osteoblasts. Using a whole-genome microarray approach, we demonstrate that C5a activates mitogen-activated protein kinases (MAPKs) and regulates the expression of genes involved in pathways related to insulin, transforming growth factor-ß and the activator protein-1 transcription factor. Interestingly, using coimmunoprecipitation, we found an interaction between C5aR1 and Toll-like receptor 2 (TLR2) in osteoblasts. The C5aR1- and TLR2-signalling pathways converge on the activation of p38 MAPK and the generation of C-X-C motif chemokine 10, which functions, among others, as an osteoclastogenic factor. In conclusion, C5a-stimulated osteoblasts might modulate osteoclast activity and contribute to immunomodulation in inflammatory bone disorders.


Assuntos
Quimiocina CXCL10/genética , Complemento C5a/genética , Inflamação/genética , Receptor da Anafilatoxina C5a/genética , Receptor 2 Toll-Like/genética , Anafilatoxinas/genética , Anafilatoxinas/imunologia , Anafilatoxinas/metabolismo , Animais , Doenças Ósseas/genética , Doenças Ósseas/imunologia , Doenças Ósseas/patologia , Remodelação Óssea/genética , Complemento C5a/imunologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Imunidade Inata/genética , Inflamação/imunologia , Inflamação/patologia , Camundongos , Osteoblastos/imunologia , Osteoblastos/metabolismo , Osteoclastos/imunologia , Osteoclastos/metabolismo , Osteogênese/genética , Osteogênese/imunologia , Transdução de Sinais , Fator de Crescimento Transformador beta/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
10.
Biochem Biophys Res Commun ; 504(4): 679-685, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30213634

RESUMO

Wnt5a signalling plays pathological roles in synovial inflammation and bone destruction. In the present study, we designed four human Wnt5a-based DNA recombinants and detected their effects on immunogenicity and anti-rheumatism in a collagen-induced arthritis (CIA) model. Histomorphometry and micro-CT scanning showed that the phWnt5a-NL was superior to other recombinants because it resulted in decreased severity of arthritis, histopathological scores of synovial inflammation and bone erosion in CIA mice. In addition, ELISA and TRAP staining showed that the phWnt5a-NL-immunized CIA mice had reductions in the serum concentrations of the rheumatoid-associated cytokines IL-1ß and RANKL and in osteoclastogenesis. Furthermore, flow cytometry showed that the phWnt5a-NL treatment increased the percentage of Treg cells. Finally, western blotting analysis showed that the phWnt5a-NL-immunization interrupted ß-catenin and JNK expression in osteoclast precursors derived from the CIA mice. The results suggest that depleting the carboxy-terminus in hWnt5a-based DNA recombinants may be beneficial for the treatment of chronic inflammatory disorders involving bone resorption.


Assuntos
Artrite Experimental/imunologia , Imunização/métodos , Proteínas Recombinantes/imunologia , Proteína Wnt-5a/imunologia , Animais , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/patologia , Citocinas/sangue , Citocinas/imunologia , Humanos , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Osteoclastos/citologia , Osteoclastos/imunologia , Osteoclastos/metabolismo , Osteogênese/imunologia , Proteínas Recombinantes/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo , Microtomografia por Raio-X/métodos
11.
Immunol Lett ; 203: 80-86, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30213687

RESUMO

Poly-γ-glutamic acid (γ-PGA), a natural polymer derived from Bacillus subtilis, shows anti-inflammatory activity. However, the effects of γ-PGA on osteoclasts, which are important cells for joint destruction in inflammatory diseases such as rheumatoid arthritis (RA), have not yet been reported. In this study, we show that γ-PGA markedly inhibits osteoclast differentiation in normal PBMC-derived osteoclast precursors and in synovial fluid macrophages of patients with RA. γ-PGA also reduces RANK expression by down-regulating M-CSF receptors. Additionally, oral administration of γ-PGA attenuated bone destruction in a collagen-induced arthritis (CIA) model, demonstrating decreases in inflammation, cartilage damage, and osteoclast formation in histological analyses. Taken together, these data suggest that γ-PGA could be a good candidate for therapeutic prevention of joint destruction in RA.


Assuntos
Artrite Experimental , Osteoclastos , Osteogênese , Ácido Poliglutâmico/análogos & derivados , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Humanos , Masculino , Camundongos , Osteoclastos/imunologia , Osteoclastos/patologia , Osteogênese/efeitos dos fármacos , Osteogênese/imunologia , Ácido Poliglutâmico/farmacologia
12.
Immunobiology ; 223(12): 761-771, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30107932

RESUMO

Complement system is an important arm of the immune system that promotes inflammation. Complement Factor H (FH) is a critical regulator of the alternative complement pathway. Its absence causes pathology in different organs resulting in diseases such as age related macular degeneration and dense deposit disease. Recent studies suggest that the complement system plays a role in bone development and homeostasis. To determine the role of FH in bone architecture, we studied the FH knockout (fh-/-) mice. 3D reconstructions of femur from 16 week old fh-/- mice reveal significant changes, such as decreased BV/TV (4.5%, p < 0.02), trabecular number (22%, p < 0.01), tissue mineral density (16%, p < 0.04), and increased marrow area (16% p < 0.01), compared to their wild type (WT) counterparts. Kidney function and histology remained normal indicating that bone changes occurred prior to kidney dysfunction. Next we examined cultured osteoblasts and osteoclasts isolated from bone marrow. FH is expressed ubiquitously in the osteoblasts and in the cytoplasm of osteoclasts. The changes caused by absence of FH include: increase in number of osteoblasts (362%) and osteoclasts (342%), increase in RNA (180%) and protein expression of cathepsin K and increased osteoclast function (pit formation, 233%). Actin rearrangement in both osteoblasts and osteoclasts was altered, with a loss of integrity of the F-actin ring at the periphery of the osteoclasts. For the first time our studies demonstrate a direct role of FH in the maintenance of bone structure and function and is highlighted as a promising therapeutic target in bone diseases.


Assuntos
Osso e Ossos/imunologia , Osso e Ossos/metabolismo , Fator H do Complemento/imunologia , Actinas/metabolismo , Animais , Biomarcadores , Reabsorção Óssea/genética , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Imunofluorescência , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Osteoblastos/imunologia , Osteoblastos/metabolismo , Osteoclastos/imunologia , Osteoclastos/metabolismo , Fenótipo , Microtomografia por Raio-X
13.
Int J Mol Med ; 42(4): 2071-2079, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30066839

RESUMO

Osteoimmunological studies have revealed that T cells exert a powerful impact on the formation and activity of osteoclasts and bone remodeling. Evidence demonstrates that immature dendritic cells (iDCs) are more efficient transdifferentiating into osteoclasts (OCs) than monocytes. However, whether Vγ9Vδ2 T (γδ T) cells stimulate or inhibit iDC transdifferentiation into OCs has never been reported. The aim of the present study was to investigate the effects of γδ T cells on this transdifferentiation process. γδ T cells and iDCs were isolated from the peripheral blood of healthy volunteers separately and were co­cultured with Transwelll inserts, with γδ T cells in the upper chamber and iDCs in the lower chamber. IDCs were treated with macrophage­colony stimulating factor and receptor activator of nuclear factor­κB (RANK) ligand. Tartrate resistant acid phosphatase (TRAP) assay and dentine resorption assay were performed to detect OC formation and their resorption capacity, respectively. The mRNA expression of OCs was examined using a microarray and real time­quantitative polymerase chain reaction to trace the changes during iDC transdifferentiation into OCs. The results demonstrated that γδ T cells significantly inhibited the generation of the TRAP­positive OCs from iDCs and their resorption capacity. The microarray analysis identified decreased expression level of Fos proto­oncogene AP­1 transcription factor subunit (c­Fos), ATPase H+ transporting V0 subunit d (ATP6V0D2) and cathepsin K when iDCs were co­cultured with γδ T cells. These genes are associated with OC differentiation, indicating that γδ T cells suppressed iDCs osteoclastogenesis by downregulation of the RANK/c­Fos/ATP6V0D2 signaling pathway. The present findings provide novel insights into the interactions between human γδ T cells and iDCs, and demonstrate that γδ T cells are capable of inhibiting OC formation and their activity via downregulation of genes associated with OC differentiation.


Assuntos
Transdiferenciação Celular/imunologia , Células Dendríticas/imunologia , Osteoclastos/imunologia , Proteínas Proto-Oncogênicas c-fos/imunologia , Receptor Ativador de Fator Nuclear kappa-B/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , ATPases Vacuolares Próton-Translocadoras/imunologia , Células Dendríticas/patologia , Humanos , Osteoclastos/patologia , Linfócitos T/patologia
14.
PLoS One ; 13(8): e0202583, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30118518

RESUMO

Rheumatoid arthritis (RA) has a negative impact on bone that is partly mediated by anti-citrullinated proteins antibodies (ACPA). These antibodies are associated with erosions, and with juxta-articular and systemic bone loss. Other RA autoantibodies, the anti-carbamylated protein antibodies (anti-CarPA), are independently associated with erosions. However, we do not know if they are also associated with juxta-articular and systemic bone loss. Here, we have addressed this question with data from 548 early arthritis (EA) patients. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry at the lumbar spine (LS), total hip (TH) and metacarpophalangeal joints (MCP). The 25.9% anti-CarPA positive patients did not show significant differences in BMD Z-scores with the negative patients. Nevertheless, this result was due to the similarity between negative and low-positive (below the median of the positive) patients, whereas the high-positive patients showed significant decrease of BMD at LS (ß = -0.39, p = 0.01) and TH (ß = -0.30, p = 0.02); but not at the juxta-articular bone of MCP. Given the overlap between anti-CarPA and ACPA, we included the two autoantibodies in an analysis that showed significantly lower BMD Z-scores at LS and TH (p< 0.01) only in the ACPA positive/anti-CarPA high-positive subgroup. However, the similar coefficients of regression between the ACPA positive/anti-CarPA high-positive and the ACPA negative/anti-CarPA high-positive subgroups (ß = -0.50 vs. -0.52 at LS, and ß = -0.37 vs. -0.30 at TH) suggested an independent association. Overall, these results support a contribution of anti-CarPA to systemic bone loss in EA patients.


Assuntos
Artrite Reumatoide/fisiopatologia , Densidade Óssea , Reabsorção Óssea/fisiopatologia , Osteólise/fisiopatologia , Absorciometria de Fóton , Adulto , Idoso , Anticorpos Anti-Proteína Citrulinada/sangue , Anticorpos Anti-Proteína Citrulinada/imunologia , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Anti-Idiotípicos/imunologia , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico por imagem , Autoanticorpos/sangue , Autoanticorpos/imunologia , Reabsorção Óssea/sangue , Reabsorção Óssea/complicações , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/fisiopatologia , Masculino , Articulação Metacarpofalângica/fisiopatologia , Pessoa de Meia-Idade , Osteoclastos/imunologia , Osteoclastos/patologia , Osteólise/complicações , Osteólise/diagnóstico por imagem , Carbamilação de Proteínas/imunologia
15.
J Cell Mol Med ; 22(9): 4399-4409, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29992753

RESUMO

Endogenous nucleic acids and their receptors may be involved in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). As the role of the DNA sensing Toll-like receptor (TLR) 9 in RA is unclear, we aimed to investigate its involvement in the pathogenesis of autoimmune arthritis using three different experimental models of RA. The data obtained revealed involvement of TLR9 in the T cell-dependent phase of inflammatory arthritis. In rats with pristane-induced arthritis (PIA), TLR9 inhibition before disease onset reduced arthritis significantly and almost completely abolished bone erosion. Accordingly, serum levels of IL-6, α-1-acid-glycoprotein and rheumatoid factor were reduced. Moreover, in TLR9-/- mice, streptococcal cell wall (SCW)-induced arthritis was reduced in the T cell-dependent phase, whereas T cell-independent serum-transfer arthritis was not affected. Remarkably, while TLR7 expression did not change during in vitro osteoclastogenesis, TLR9 expression was higher in precursor cells than in mature osteoclasts and partial inhibition of osteoclastogenesis was achieved only by the TLR9 antagonist. These results demonstrate a pivotal role for TLR9 in the T cell-dependent phases of inflammatory arthritis and additionally suggest some role during osteoclastogenesis. Hence, endogenous DNA seems to be crucially involved in the pathophysiology of inflammatory autoimmune arthritis.


Assuntos
Artrite Experimental/genética , Articulações/imunologia , Osteoclastos/imunologia , Osteogênese/genética , Receptor Toll-Like 9/genética , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/patologia , Cartilagem Articular/imunologia , Cartilagem Articular/patologia , Parede Celular/química , Misturas Complexas/administração & dosagem , Regulação da Expressão Gênica , Interleucina-6/genética , Interleucina-6/imunologia , Articulações/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orosomucoide/genética , Orosomucoide/imunologia , Osteoclastos/patologia , Ratos , Fator Reumatoide/genética , Fator Reumatoide/imunologia , Transdução de Sinais , Streptococcus pyogenes/química , Terpenos/administração & dosagem , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor Toll-Like 9/deficiência , Receptor Toll-Like 9/imunologia
16.
Hum Pathol ; 81: 157-165, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30031096

RESUMO

Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has a striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1, and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extrapancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas were immunostained using antibodies against PD-1, PD-L1, and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17 (63%) of 27 cases, more often in cases with an associated PDAC (P = .04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than did patients with PD-L1-negative UCOGCs (hazard ratio, 3.397; 95% confidence interval, 1.023-18.375; P = .034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P = .035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extrapancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. Anaplastic carcinomas have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma Ductal Pancreático/imunologia , Diferenciação Celular , Células Gigantes/imunologia , Osteoclastos/imunologia , Neoplasias Pancreáticas/imunologia , Receptor de Morte Celular Programada 1/análise , Receptores de Superfície Celular/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Europa (Continente) , Feminino , Células Gigantes/patologia , Histiócitos/química , Histiócitos/patologia , Humanos , Imuno-Histoquímica , Indiana , Linfócitos/imunologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Osteoclastos/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Fenótipo
17.
Arthritis Res Ther ; 20(1): 80, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29720243

RESUMO

BACKGROUND: Osteoclast-mediated bone erosion is a central feature of rheumatoid arthritis (RA). Immune complexes, present in a large percentage of patients, bind to Fcγ receptors (FcγRs), thereby modulating the activity of immune cells. In this study, we investigated the contribution of FcγRs, and FcγRIV in particular, during antigen-induced arthritis (AIA). METHODS: AIA was induced in knee joints of wild-type (WT), FcγRI,II,III-/-, and FcγRI,II,III,IV-/- mice. Bone destruction, numbers of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts, and inflammation were evaluated using histology; expression of the macrophage marker F4/80, neutrophil marker NIMPR14, and alarmin S100A8 was evaluated using immunohistochemistry. The percentage of osteoclast precursors in the bone marrow was determined using flow cytometry. In vitro osteoclastogenesis was evaluated with TRAP staining, and gene expression was assessed using real-time PCR. RESULTS: FcγRI,II,III,IV-/- mice showed decreased bone erosion compared with WT mice during AIA, whereas both the humoral and cellular immune responses against methylated bovine serum albumin were not impaired in FcγRI,II,III,IV-/- mice. The percentage of osteoclast precursors in the bone marrow of arthritic mice and their ability to differentiate into osteoclasts in vitro were comparable between FcγRI,II,III,IV-/- and WT mice. In line with these observations, numbers of TRAP+ osteoclasts on the bone surface during AIA were comparable between the two groups. Inflammation, a process that strongly activates osteoclast activity, was reduced in FcγRI,II,III,IV-/- mice, and of note, mainly decreased numbers of neutrophils were present in the joint. In contrast to FcγRI,II,III,IV-/- mice, AIA induction in knee joints of FcγRI,II,III-/- mice resulted in increased bone erosion, inflammation, and numbers of neutrophils, suggesting a crucial role for FcγRIV in the joint pathology by the recruitment of neutrophils. Finally, significant correlations were found between bone erosion and the number of neutrophils present in the joint as well as between bone erosion and the number of S100A8-positive cells, with S100A8 being an alarmin strongly produced by neutrophils that stimulates osteoclast resorbing activity. CONCLUSIONS: FcγRs play a crucial role in the development of bone erosion during AIA by inducing inflammation. In particular, FcγRIV mediates bone erosion in AIA by inducing the influx of S100A8/A9-producing neutrophils into the arthritic joint.


Assuntos
Artrite Experimental/imunologia , Osso e Ossos/imunologia , Calgranulina A/imunologia , Calgranulina B/imunologia , Neutrófilos/imunologia , Receptores de IgG/imunologia , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Articulação do Joelho/imunologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/metabolismo , Osteoclastos/imunologia , Osteoclastos/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Fosfatase Ácida Resistente a Tartarato/imunologia , Fosfatase Ácida Resistente a Tartarato/metabolismo
18.
J Immunol Res ; 2018: 5783639, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29725604

RESUMO

Glucagon-like peptide-1 (GLP-1) receptor agonists are an effective treatment approach for type 2 diabetes. Recently, anti-inflammatory effects of GLP-1 receptor agonists have also been reported. Lipopolysaccharide (LPS) induces inflammation and osteoclast formation. In this study, we investigated the effect of exendin-4, a widely used GLP-1 receptor agonist, in LPS-induced osteoclast formation and bone resorption. LPS with or without exendin-4 was administered on mouse calvariae by daily subcutaneous injection. The number of osteoclasts, the ratio of bone resorption pits, and the level of C-terminal cross-linked telopeptide of type I collagen (CTX) were significantly lower in LPS- and exendin-4-coadministered mice than in mice administered with LPS alone. RANKL and TNF-α mRNA expression levels were lower in the exendin-4- and LPS-coadministered group than in the LPS-administered group. Our in vitro results showed no direct effects of exendin-4 on RANKL-induced osteoclast formation, TNF-α-induced osteoclast formation, or LPS-induced RANKL expression in stromal cells. Conversely, TNF-α mRNA expression was inhibited in the exendin-4- and LPS-cotreated macrophages compared with cells treated with LPS alone. These results indicate that the GLP-1 receptor agonist exendin-4 may inhibit LPS-induced osteoclast formation and bone resorption by inhibiting LPS-induced TNF-α production in macrophages.


Assuntos
Anti-Inflamatórios/farmacologia , Reabsorção Óssea/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Macrófagos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Peptídeos/farmacologia , Peçonhas/farmacologia , Animais , Diferenciação Celular , Células Cultivadas , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/imunologia , Fator de Necrose Tumoral alfa/metabolismo
19.
Matrix Biol ; 71-72: 70-81, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29738833

RESUMO

Bone loss in women accelerates during perimenopause, and continues into old age. To-date, there has been little progress made in stratifying for fracture risk in premenopausal and early postmenopausal women. Epidemiologic data suggests that changes in serum FSH could predict decrements in bone mass during peri- and postmenopause. In bone, FSH stimulates osteoclast formation by releasing osteoclastogenic cytokines. Here, we address the evidence for bone loss across the menopausal transition, discuss strategies for detection and treatment of early postmenopausal osteoporosis, and describe the role FSH plays in physiology and likely in pathophysiology of early postmenopausal bone loss.


Assuntos
Hormônio Foliculoestimulante/sangue , Osteoporose/epidemiologia , Osteoporose/patologia , Perimenopausa/metabolismo , Adulto , Citocinas/metabolismo , Gerenciamento Clínico , Diagnóstico Precoce , Feminino , Humanos , Pessoa de Meia-Idade , Osteoclastos/imunologia , Osteoporose/imunologia , Osteoporose/metabolismo , Perimenopausa/sangue , Perimenopausa/imunologia
20.
Biochem Biophys Res Commun ; 501(2): 547-555, 2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29746861

RESUMO

Osteolytic diseases are closely associated with osteocyte fate, indicating a more efficient and crucial role of osteocyte-targeting strategy in inhibiting osteoclastogenesis. Here, we investigated the effects of lenalidomide (Lena) on osteocyte fate in order to regulate osteoclastogenesis via effective cascade-controlling response. Our data revealed that lenalidomide treatment notably rescued IL-1ß induced loss of osteocyte viability by inhibiting osteocyte apoptosis with decreased osteoclast-related factors, RANKL and Sclerostin, as demonstrated by the restricted osteoclast formation and reduced bone resorption. Additionally, iTRAQ assay revealed that IL-1ß induced activation of NF-κB inhibitor α/ß were remarkably downregulated by lenalidomide, showing that lenalidomide impaired NF-κB signaling in osteocytes for inhibiting the expression of osteoclast specific genes in osteoclasts, which was further confirmed by KEGG pathway analysis and Western blot. More interestingly, the in vivo analysis of osteocyte apoptosis and osteoclastogenesis in osteoarthritis mice model indicated a role of lenalidomide in the regulation of osteocyte fate and the consequent inhibition of RANKL-induced osteoclastogenesis. Together, these results suggest that lenalidomide regulates osteocyte fate by attenuating IL-1ß/NF-κB signaling, thereby inhibiting RANKL expression for the attenuated osteoclastogenesis both in vitro and vivo, indicating a more efficient remedy among future anti-osteoclastogenesis approaches.


Assuntos
Fatores Imunológicos/farmacologia , Interleucina-1beta/imunologia , NF-kappa B/imunologia , Osteócitos/efeitos dos fármacos , Ligante RANK/imunologia , Transdução de Sinais/efeitos dos fármacos , Talidomida/análogos & derivados , Animais , Linhagem Celular , Células Cultivadas , Lenalidomida , Camundongos Endogâmicos C57BL , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteócitos/citologia , Osteócitos/imunologia , Osteogênese/efeitos dos fármacos , Talidomida/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA