RESUMO
Alloxan (ALX) and streptozotocin (STZ) are extensively used to induce type 1 diabetes (T1D) in animal models. This study is aimed at evaluating the differences in immune parameters caused by ALX and STZ. T1D was induced either with ALX or with STZ, and the animals were followed for up to 180 days. Both ALX and STZ induced a decrease in the total number of circulating leukocytes and lymphocytes, with an increase in granulocytes when compared to control mice (CT). STZ-treated mice also exhibited an increase in neutrophils and a reduction in the lymphocyte percentage in the bone marrow. In addition, while the STZ-treated group showed a decrease in total CD3+, CD4-CD8+, and CD4+CD8+ T lymphocytes in the thymus and CD19+ B lymphocytes in the pancreas and spleen, the ALX group showed an increase in CD4-CD8+ and CD19+ only in the thymus. Basal levels of splenic interleukin- (IL-) 1ß and pancreatic IL-6 in the STZ group were decreased. Both diabetic groups showed atrophy of the thymic medulla and degeneration of pancreatic islets of Langerhans composed of inflammatory infiltration and hyperemia with vasodilation. ALX-treated mice showed a decrease in reticuloendothelial cells, enhanced lymphocyte/thymocyte cell death, and increased number of Hassall's corpuscles. Reduced in vitro activation of splenic lymphocytes was found in the STZ-treated group. Furthermore, mice immunized with ovalbumin (OVA) showed a more intense antigen-specific paw edema response in the STZ-treated group, while production of anti-OVA IgG1 antibodies was similar in both groups. Thereby, important changes in immune cell parameters in vivo and in vitro were found at an early stage of T1D in the STZ-treated group, whereas alterations in the ALX-treated group were mostly found in the chronic phase of T1D, including increased mortality rates. These findings suggest that the effects of ALX and STZ influenced, at different times, lymphoid organs and their cell populations.
Assuntos
Aloxano/toxicidade , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Linfócitos/efeitos dos fármacos , Estreptozocina/toxicidade , Animais , Glicemia/análise , Citocinas/biossíntese , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Baço/efeitos dos fármacos , Baço/imunologia , Timo/efeitos dos fármacos , Timo/patologiaRESUMO
Periodontitis is an inflammatory disease that affects the supporting structures of teeth. The presence of a bacterial biofilm initiates a destructive inflammatory process orchestrated by various inflammatory mediators, most notably proinflammatory cytokines, which are upregulated in the gingival crevicular fluid, leading to the formation of periodontal pockets. This represents a well-characterized microbial change during the transition from periodontal health to periodontitis; interestingly, the gestational condition increases the risk and severity of periodontal disease. Although the influence of periodontitis on pregnancy has been extensively reviewed, the relationship between pregnancy and the development/evolution of periodontitis has been little studied compared to the effect of periodontitis on adverse pregnancy outcomes. This review is aimed at summarizing the findings on the pregnancy-proinflammatory cytokine relationship and discussing its possible involvement in the development of periodontitis. We address (1) an overview of periodontal disease, (2) the immune response and possible involvement of proinflammatory cytokines in the development of periodontitis, (3) how bone tissue remodelling takes place with an emphasis on the involvement of the inflammatory response and metalloproteinases during periodontitis, and (4) the influence of hormonal profile during pregnancy on the development of periodontitis. Finally, we believe this review may be helpful for designing immunotherapies based on the stage of pregnancy to control the severity and pathology of periodontal disease.
Assuntos
Bactérias/imunologia , Citocinas/biossíntese , Hormônios Esteroides Gonadais/fisiologia , Periodontite/imunologia , Remodelação Óssea , Feminino , Microbioma Gastrointestinal/fisiologia , Humanos , Metaloproteases/fisiologia , Periodontite/etiologia , Periodontite/microbiologia , Gravidez , Complicações na Gravidez/etiologia , Complicações na Gravidez/imunologiaRESUMO
BACKGROUND: Cold temperatures can aggravate pulmonary diseases and promote pulmonary arterial hypertension (PAH); however, the underlying mechanism has not been fully explored. AIM: To explore the effect of chronic cold exposure on the production of inflammatory cytokines and microRNAs (miRNAs) in a monocrotaline (MCT)-induced PAH model. METHODS: Male Sprague Dawley rats were divided into a Control (23.5 ± 2 °C), Cold (5.0 ± 1 °C for ten days), MCT (60 mg/kg body weight i.p.), and MCT + Cold (ten days of cold exposure after 3 weeks of MCT injection). Hemodynamic parameters, right ventricle (RV) hypertrophy, and pulmonary arterial medial wall thickness were determined. IL-1ß, IL-6, and TNF-α levels were determined using western blotting. miR-21-5p and -3p, miR-146a-5p and -3p, and miR-155-5p and -3p and plasma extracellular vesicles (EVs) and mRNA expression of Cd68, Cd163, Bmpr2, Smad5, Tgfbr2, and Smad3 were determined using RT-qPCR. RESULTS: The MCT + Cold group had aggravated RV hypertrophy hemodynamic parameters, and pulmonary arterial medial wall thickness. In lungs of the MCT + Cold, group the protein levels of TNF-α, IL-1ß, and IL-6 were higher than those in the MCT group. The mRNA expression of Cd68 and Cd163 were higher in the MCT + Cold group. miR-146a-5p and miR-155-5p levels were higher in the plasma EVs and lungs of the MCT + Cold group. Cold exposure promoted a greater decrease in miR-21-5p, Bmpr2, Smad5, Tgfbr2, and Smad3 mRNA expression in lungs of the MCT + Cold group. CONCLUSION: Cold exposure aggravates MCT-induced PAH with an increase in inflammatory marker and miRNA levels in the plasma EVs and lungs.
Assuntos
Temperatura Baixa/efeitos adversos , Citocinas/biossíntese , MicroRNAs/biossíntese , Hipertensão Arterial Pulmonar/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Animais , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Pulmão/metabolismo , Pulmão/patologia , Masculino , Hipertensão Arterial Pulmonar/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Silicosis is a lethal pneumoconiosis for which no therapy is available. Silicosis is a global threat, and more than 2.2 million people per year are exposed to silica in the United States. The initial response to silica is mediated by innate immunity. Phagocytosis of silica particles by macrophages is followed by recruitment of mitochondria to phagosomes, generation of mitochondrial reactive oxygen species, and cytokine (IL-1ß, TNF-α, IFN-ß) release. In contrast with LPS, the metabolic remodeling of silica-exposed macrophages is unclear. This study contrasts mitochondrial and metabolic alterations induced by LPS and silica on macrophages and correlates them with macrophage viability and cytokine production, which are central to the pathogenesis of silicosis. Using high-resolution respirometer and liquid chromatography-high-resolution mass spectrometry, we determined the effects of silica and LPS on mitochondrial respiration and determined changes in central carbon metabolism of murine macrophage cell lines RAW 264.7 and IC-21. We show that silica induces metabolic reprogramming of macrophages. Silica, as well as LPS, enhances glucose uptake and increases aerobic glycolysis in macrophages. In contrast with LPS, silica affects mitochondria respiration, reducing complex I and enhancing complex II activity, to sustain cell viability. These mitochondrial alterations are associated in silica, but not in LPS-exposed macrophages, with reductions of tricarboxylic acid cycle intermediates, including succinate, itaconate, glutamate, and glutamine. Furthermore, in contrast with LPS, these silica-induced metabolic adaptations do not correlate with IL-1ß or TNF-α production, but with the suppressed release of IFN-ß. Our data highlight the importance of complex II activity and tricarboxylic acid cycle remodeling to macrophage survival and cytokine-mediated inflammation in silicosis.
Assuntos
Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Silicose/imunologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Ciclo do Ácido Cítrico/efeitos dos fármacos , Cristalização , Citocinas/biossíntese , Inflamação/imunologia , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fagocitose/efeitos dos fármacos , Fagossomos/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Silicose/metabolismoRESUMO
Cardiac fibroblasts (CF) play an important role in the healing process and in pathological remodeling of cardiac tissue. As sentinel cells in the heart, they respond to inflammatory stimuli, expressing cytokines and cell adhesion proteins, which ultimately lead to increased recruitment of monocytes and enhancement of the inflammatory response. Angiotensin II (Ang II) triggers an inflammatory response, leading to cardiac tissue remodeling. On the other hand, RvD1 has been shown to contribute to the resolution of inflammation; however, its role in Ang II-treated CF has not been addressed until now. The present research aimed to study the effect of RvD1 on cytokine levels, cell adhesion proteins expression in a model of Ang II-triggered inflammatory response. CF from adult Sprague Dawley rats were used to study mRNA and protein levels of MCP-1, IL-6, TNF-a, IL-10, ICAM-1 and VCAM-1; and adhesion of spleen mononuclear cells to CF after Ang II stimulation. Our results show that Ang II increased IL-6, MCP-1 and TNF-a mRNA levels, but only increased IL-6 and MCP-1 protein levels. These effects were blocked by Losartan, but not by PD123369. Moreover, RvD1 was able to prevent all Ang II effects in CF. Additionally, RvD1 reduced the intracellular Ca2+ increase triggered by Ang II, indicating that RvD1 acts in an early manner to block Ang II signaling. Conclusion: our findings confirm the pro-resolutive effects of inflammation by RvD1, which at the cardiovascular level, could contribute to repair damaged cardiac tissue.
Assuntos
Angiotensina II/toxicidade , Adesão Celular/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Ácidos Docosa-Hexaenoicos/farmacologia , Monócitos/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Adesão Celular/fisiologia , Células Cultivadas , Citocinas/biossíntese , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Expressão Gênica , Masculino , Monócitos/metabolismo , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Zika virus (ZIKV), alongside Dengue virus (DENV), Chikungunya virus (CHIKV), and Yellow Fever Virus (YFV) are prevalent arboviruses in the Americas. Each of these infections is associated with the development of associated disease immunopathology. Immunopathological processes are an outcome of counter-balancing impacts between effector and regulatory immune mechanisms. In this context, regulatory T cells (Tregs) are key in modulating the immune response and, therefore, in tissue damage control. However, to date, Treg phenotypes and mechanisms during acute infection of the ZIKV in humans have not been fully investigated. The main aim of this work was to characterize Tregs and their immunological profile related to cytokine production and molecules that are capable of controlling the exacerbated inflammatory profile in acute Zika infected patients. Using whole blood analyses of infected patients, an ex vivo phenotypical characterization of Tregs, circulating during acute Zika virus infection, was conducted by flow cytometry. We found that though there are no differences in absolute Treg frequency between infected and healthy control groups. However, pro-inflammatory cytokine up-regulation such as IFN-γ and LAP was observed in the acute disease. Furthermore, acute ZIKV patients expressed increased levels of CD39/CD73, perforin/granzyme B, PD-1, and CTLA-4, all markers involved in mechanisms used by Tregs to attempt to control strong inflammatory responses. Thus, the data indicates a potential contribution of Tregs during the inflammatory ZIKV infection response.
Assuntos
Linfócitos T Reguladores/imunologia , Infecção por Zika virus/imunologia , Adulto , Estudos de Casos e Controles , Morte Celular , Citocinas/biossíntese , Feminino , Humanos , Masculino , Fenótipo , Linfócitos T Reguladores/metabolismo , Zika virus/imunologia , Infecção por Zika virus/patologia , Infecção por Zika virus/virologiaRESUMO
Lignins are phenolic macromolecules that have several applications. In this work, we examine some biological activities of a lignin-like macromolecule isolated from the Crataeva tapia leaves, not yet studied to evaluate its potential applications in medicinal and cosmetic formulations. Lignin was obtained by alkaline delignification and its physical-chemical characterization was made by means of FT-IR, UV-Vis, NMR spectroscopy, elementary analysis, molecular mass determination and thermal analysis. Lignin is of the GSH type, with levels of hydrogen (5.10%), oxygen (27.18%), carbon (67.60%), nitrogen (0.12%) and phenolic content of 189.6 ± 9.6 mg GAE/g. In addition, it is a thermally stable macromolecule with low antioxidant activity. Cytotoxicity and cytokine production were assessed by flow cytometry. The photoprotective activity was evaluated by adding different concentrations of lignin to a commercial cream. Lignin was not cytotoxic, it stimulated the production of TNF-α, IL-6 and IL-10 and did not promote a significant change in nitric oxide levels. In addition, this macromolecule was able to promote increased absorption of ultraviolet light from a commercial cream. These results reinforce the ethnopharmacological use of C. tapia leaves and suggest the need for further studies to determine the potential medicinal and cosmetic applications (sunscreen) of lignin from C. tapia leaves.
Assuntos
Antioxidantes/química , Capparaceae/química , Lignina/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Protetores Solares/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Doadores de Sangue , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cosméticos/química , Citocinas/biossíntese , Humanos , Lignina/isolamento & purificação , Lignina/farmacologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Peso Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fenóis/análise , Extratos Vegetais/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Protetores Solares/isolamento & purificação , Protetores Solares/farmacologia , Raios UltravioletaRESUMO
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction associated with increased pro-inflammatory mediators. In inflammatory microenvironments, exogenous ATP (eATP) is hydrolyzed to adenosine, which exerts immunosuppressive effects, by the consecutive action of the ectonucleotidases CD39 and CD73. Mature B cells constitutively express both ectonucleotidases, converting these cells to potential suppressors. Here, we assessed CD39 and CD73 expression on B cells from treated or untreated patients with RA. Neither the frequency of CD73+CD39+ and CD73-CD39+ B cell subsets nor the levels of CD73 and CD39 expression on B cells from untreated or treated RA patients showed significant changes in comparison to healthy controls (HC). CpG+IL-2-stimulated B cells from HC or untreated RA patients increased their CD39 expression, and suppressed CD4+ and CD8+ T cell proliferation and intracellular TNF-production. A CD39 inhibitor significantly restored proliferation and TNF-producing capacity in CD4+ T cells, but not in CD8+ T cells, from HC and untreated RA patients, indicating that B cells from untreated RA patients conserved CD39-mediated regulatory function. Good responder patients to therapy (R-RA) exhibited an increased CD39 but not CD73 expression on B cells after treatment, while most of the non-responder (NR) patients showed a reduction in ectoenzyme expression. The positive changes of CD39 expression on B cells exhibited a negative correlation with disease activity and rheumatoid factor levels. Our results suggest modulating the ectoenzymes/ADO pathway as a potential therapy target for improving the course of RA.
Assuntos
Apirase/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Imunomodulação , Adenosina/metabolismo , Apirase/genética , Artrite Reumatoide/patologia , Artrite Reumatoide/terapia , Linfócitos B Reguladores/imunologia , Linfócitos B Reguladores/metabolismo , Estudos de Casos e Controles , Citocinas/biossíntese , Gerenciamento Clínico , Suscetibilidade a Doenças , Expressão Gênica , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: The thermodimorphic fungi Paracoccidioides spp. are the etiological agents of paracoccidioidomycosis. Although poorly studied, paracoccin (PCN) from Paracoccidioides brasiliensis has been shown to harbor lectinic, enzymatic, and immunomodulatory properties that affect disease development. METHODS: Mutants of P. brasiliensis overexpressing PCN (ov-PCN) were constructed by Agrobacterium tumefaciens-mediated transformation. ov-PCN strains were analyzed and inoculated intranasally or intravenously to mice. Fungal burden, lung pathology, and survival were monitored to evaluate virulence. Electron microscopy was used to evaluate the size of chito-oligomer particles released by ov-PCN or wild-type strains to growth media. RESULTS: ov-PCN strains revealed no differences in cell growth and viability, although PCN overexpression favored cell separation, chitin processing that results in the release of smaller chito-oligomer particles, and enhanced virulence. Our data show that PCN triggers a critical effect in the cell wall biogenesis through the chitinase activity resulting from overexpression of PCN. As such, PCN overexpression aggravates the disease caused by P. brasiliensis. CONCLUSIONS: Our data are consistent with a model in which PCN modulates the cell wall architecture via its chitinase activity. These findings highlight the potential for exploiting PCN function in future therapeutic approaches.
Assuntos
Parede Celular/metabolismo , Quitina/metabolismo , Proteínas Fúngicas/fisiologia , Lectinas/fisiologia , Paracoccidioides/patogenicidade , Animais , Citocinas/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Paracoccidioidomicose/imunologia , Fagocitose , VirulênciaRESUMO
Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads to an altered response towards a second challenge after the return to a nonactivated state. This phenomenon is known as trained immunity (TI). TI is not only important for host defense and vaccine response but also for chronic inflammations such as cardiovascular and metabolic diseases such as atherosclerosis. TI can occur in innate immune cells such as monocytes/macrophages, natural killer cells, endothelial cells (ECs), and nonimmune cells, such as fibroblast. In this brief review, we analyze the significance of TI in ECs, which are also considered as innate immune cells in addition to macrophages. TI can be induced by a variety of stimuli, including lipopolysaccharides, BCG (bacillus Calmette-Guerin), and oxLDL (oxidized low-density lipoprotein), which are defined as risk factors for cardiovascular and metabolic diseases. Furthermore, TI in ECs is functional for inflammation effectiveness and transition to chronic inflammation. Rewiring of cellular metabolism of the trained cells takes place during induction of TI, including increased glycolysis, glutaminolysis, increased accumulation of tricarboxylic acid cycle metabolites and acetyl-coenzyme A production, as well as increased mevalonate synthesis. Subsequently, this leads to epigenetic remodeling, resulting in important changes in chromatin architecture that enables increased gene transcription and enhanced proinflammatory immune response. However, TI pathways and inflammatory pathways are separated to ensure memory stays when inflammation undergoes resolution. Additionally, reactive oxygen species play context-dependent roles in TI. Therefore, TI plays significant roles in EC and macrophage pathology and chronic inflammation. However, further characterization of TI in ECs and macrophages would provide novel insights into cardiovascular disease pathogenesis and new therapeutic targets. Graphic Abstract: A graphic abstract is available for this article.