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Helper T cells actively communicate with adjacent cells by secreting soluble mediators, yet crosstalk between helper T cells and endothelial cells remains poorly understood. Here we found that placental growth factor (PlGF), a homolog of the vascular endothelial growth factor that enhances an angiogenic switch in disease, was selectively secreted by the TH17 subset of helper T cells and promoted angiogenesis. Interestingly, the 'angio-lymphokine' PlGF, in turn, specifically induced the differentiation of pathogenic TH17 cells by activating the transcription factor STAT3 via binding to its receptors and replaced the activity of interleukin-6 in the production of interleukin-17, whereas it suppressed the generation of regulatory T cells. Moreover, T cell-derived PlGF was required for the progression of autoimmune diseases associated with TH17 differentiation, including experimental autoimmune encephalomyelitis and collagen-induced arthritis, in mice. Collectively, our findings provide insights into the PlGF-dictated links among angiogenesis, TH17 cell development and autoimmunity.
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Artrite Experimental/imunologia , Encefalomielite Autoimune Experimental/imunologia , Fator de Crescimento Placentário/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Autoimunidade , Diferenciação Celular , Células Cultivadas , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Neovascularização Patológica , Fator de Crescimento Placentário/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismoRESUMO
Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopaminergic neurons and neuroinflammation. Recent studies have identified a role of T cells in the pathogenesis of PD. Additionally, these studies suggested that α-synuclein (α-Syn) is related to abnormal T-cell responses and may act as an epitope and trigger autoimmune T-cell responses. However, it is unclear whether the α-Syn-mediated autoimmune response occurs and whether it is related to neuronal cell death and glial cell activation. In this study, we investigated the autoimmune T-cell response induced by α-Syn peptides and evaluated the neurotoxic effect of the α-Syn peptide-mediated autoimmune response. The immunization of mice with α-Syn peptides resulted in enhanced autoimmune responses, such as the peptide recall response, polarization toward Th1/Th17 cells, and regulatory T cell imbalance. Furthermore, the α-Syn autoimmune response led to the death of primary neurons cocultured with splenocytes. Treatment with conditioned media from α-Syn peptide-immunized splenocytes induced microglia and toxic A1-type astrocyte activation. Taken together, our results provide evidence of the potential role of the α-Syn-initiated autoimmune response and its contribution to neuronal cell death and glial cell activation.
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Autoimunidade , Morte Celular , Neurônios , alfa-Sinucleína , Animais , alfa-Sinucleína/imunologia , alfa-Sinucleína/metabolismo , Camundongos , Morte Celular/efeitos dos fármacos , Neurônios/imunologia , Neurônios/metabolismo , Neurônios/patologia , Neuroglia/imunologia , Neuroglia/metabolismo , Neuroglia/efeitos dos fármacos , Doença de Parkinson/imunologia , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Camundongos Endogâmicos C57BL , Humanos , Ativação Linfocitária/imunologia , Ativação Linfocitária/efeitos dos fármacos , Peptídeos/imunologia , Células Cultivadas , Feminino , Linfócitos T Reguladores/imunologiaRESUMO
Severe fever with thrombocytopenia syndrome (SFTS) has a high mortality rate compared to other infectious diseases. SFTS is particularly associated with a high risk of mortality in immunocompromised individuals, while most patients who die of SFTS exhibit symptoms of severe encephalitis before death. However, the region of brain damage and mechanisms by which the SFTS virus (SFTSV) causes encephalitis remains unknown. Here, we revealed that SFTSV infects the brainstem and spinal cord, which are regions of the brain associated with respiratory function, and motor nerves in IFNAR1-/- mice. Further, we show that A1-reactive astrocytes are activated, causing nerve cell death, in infected mice. Primary astrocytes of SFTSV-infected IFNAR1-/- mice also induced neuronal cell death through the activation of A1-reactive astrocytes. Herein, we showed that SFTSV induces fatal neuroinflammation in the brain regions important for respiratory function and motor nerve, which may underlie mortality in SFTS patients. This study provides new insights for the treatment of SFTS, for which there is currently no therapeutic approach.
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Astrócitos , Infecções por Bunyaviridae , Camundongos Knockout , Phlebovirus , Receptor de Interferon alfa e beta , Animais , Astrócitos/virologia , Astrócitos/patologia , Camundongos , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/deficiência , Phlebovirus/genética , Phlebovirus/fisiologia , Phlebovirus/patogenicidade , Infecções por Bunyaviridae/virologia , Infecções por Bunyaviridae/patologia , Infecções por Bunyaviridae/imunologia , Encéfalo/virologia , Encéfalo/patologia , Encéfalo/imunologia , Medula Espinal/virologia , Medula Espinal/patologia , Modelos Animais de Doenças , Neurônios/virologia , Neurônios/patologia , Camundongos Endogâmicos C57BL , Tronco Encefálico/virologia , Tronco Encefálico/patologia , Morte CelularRESUMO
Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor ß1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment.
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Bleomicina/efeitos adversos , Butiratos/farmacologia , Disbiose , Fibrose Pulmonar , Dermatopatias , Animais , Bleomicina/farmacologia , Modelos Animais de Doenças , Disbiose/induzido quimicamente , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Masculino , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Dermatopatias/induzido quimicamente , Dermatopatias/tratamento farmacológico , Dermatopatias/microbiologiaRESUMO
Rheumatoid arthritis (RA) is a highly inflammatory autoimmune disease. Although proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-6, play a key role in the pathogenesis of RA, the causes of chronic inflammation are not fully understood. Here, we report that protein phosphatase magnesium-dependent 1A (PPM1A) levels were increased in RA synovial fluid compared with osteoarthritis (OA) synovial fluid and positively correlated with TNF levels. In addition, PPM1A expression was increased in synovial tissue from RA patients and joint tissue from a mouse model of arthritis. Finally, extracellular PPM1A induced inflammation by stimulating macrophages to produce TNF through toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein 88 (MyD88) signaling pathway. Our findings suggest that extracellular PPM1A may contribute to the pathogenesis of RA by functioning as a damage-associated molecular pattern (DAMP) to induce inflammation.
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Artrite Reumatoide/patologia , Inflamação/patologia , Proteína Fosfatase 2C/análise , Idoso , Animais , Células Cultivadas , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Líquido Sinovial/química , Fator de Necrose Tumoral alfa/análiseRESUMO
The lung is highly vulnerable during sepsis, yet its functional deterioration accompanied by disturbances in the pulmonary microcirculation is poorly understood. This study aimed to investigate how the pulmonary microcirculation is distorted in sepsis-induced acute lung injury (ALI) and reveal the underlying cellular pathophysiologic mechanism.Using a custom-made intravital lung microscopic imaging system in a murine model of sepsis-induced ALI, we achieved direct real-time visualisation of the pulmonary microcirculation and circulating cells in vivo We derived the functional capillary ratio (FCR) as a quantitative parameter for assessing the fraction of functional microvasculature in the pulmonary microcirculation and dead space.We identified that the FCR rapidly decreases in the early stage of sepsis-induced ALI. The intravital imaging revealed that this decrease resulted from the generation of dead space, which was induced by prolonged neutrophil entrapment within the capillaries. We further showed that the neutrophils had an extended sequestration time and an arrest-like dynamic behaviour, both of which triggered neutrophil aggregates inside the capillaries and arterioles. Finally, we found that Mac-1 (CD11b/CD18) was upregulated in the sequestered neutrophils and that a Mac-1 inhibitor restored the FCR and improved hypoxaemia.Using the intravital lung imaging system, we observed that Mac-1-upregulated neutrophil aggregates led to the generation of dead space in the pulmonary microcirculation that was recovered by a Mac-1 inhibitor in sepsis-induced ALI.
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Lesão Pulmonar Aguda/etiologia , Pulmão/irrigação sanguínea , Antígeno de Macrófago 1/imunologia , Neutrófilos/citologia , Sepse/complicações , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Anticorpos Monoclonais/farmacologia , Capilares , Modelos Animais de Doenças , Pulmão/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação , Microscopia de Vídeo , Sepse/tratamento farmacológico , Sepse/patologiaRESUMO
Inflammation and trophic factors (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor-1) are associated with depression in the general population. Rheumatoid arthritis (RA) is a chronic representative inflammatory autoimmune disease; however, the association of disease activity, pro-inflammatory cytokines, and neurotrophic factors with depression has not been sufficiently investigated. Therefore, we determined the prevalence of depression and risk factors for depression and deterioration of depressive symptoms in RA patients. In addition, we analyzed the association between disease activity, pro-inflammatory cytokines, trophic factors, and depression in RA (Nâ¯=â¯474). Demographic and laboratory data were examined, and routine assessment of patient index data 3 (RAPID 3) and disease activity score 28-joint count C-reactive protein (DAS 28-CRP) was performed to assess disease activity of RA. Depression was measured using the Korean version of the Beck Depression Inventory-second edition (K-BDI II). A K-BDI score ≥18 was considered the cut-off for depression in accordance with a previous validation study. The serum level of pro-inflammatory cytokines and neurotrophic factors was assessed by enzyme-linked immune sorbent assay. The prevalence of depression was 32.4% in patients with RA. The severity of disease activity of RA (RAPID 3 score [OR 2.34; 95% confidence interval, CI 1.22-4.51], DAS 28-CRP [≥3.2] [OR 1.60, 95% CI 1.01-2.53]) and severity of fatigue (OR 1.26 95% CI 1.15-1.38) were associated with depression and deterioration of depressive symptoms in the multivariate analysis. Among the components of RAPID 3 and DAS 28-CRP, patient assessment for global health and abilities for daily performance were more related to depression. The level of pro-inflammatory cytokines (IL-1ß, IL-6, TNF-alpha) was not related to depression. The level of BDNF was significantly lower in RA patients with depression and was negatively correlated with K-BDI II score. Depression was related with the level of fatigue, low expression of BDNF, and high RA disease activity, which was associated with impaired ability to perform activities of daily life. Strict control of fatigue and disease activity to improve one's capacity to perform daily life activities would be important to regulate depression. The level of BDNF might be one of the possible biomarkers to predict or monitor depression in patients with RA.
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Artrite Reumatoide/psicologia , Depressão/fisiopatologia , Idoso , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/análise , Fator Neurotrófico Derivado do Encéfalo/sangue , Proteína C-Reativa/análise , Estudos Transversais , Citocinas/análise , Citocinas/sangue , Depressão/epidemiologia , Depressão/imunologia , Transtorno Depressivo/epidemiologia , Feminino , Humanos , Inflamação , Interleucina-1beta/análise , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Crescimento Neural/metabolismo , Prevalência , Escalas de Graduação Psiquiátrica , Fatores de Risco , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Here, we report the case of a 69-year-old man with limited granulomatosis with polyangiitis (GPA; formerly Wegener's granulomatosis) who developed papillary thyroid cancer, adenocarcinoma of the stomach, and myelodysplastic syndrome following glucocorticoid treatment. This is the first report to present multiple malignancies in a patient with limited GPA without immunosuppressive treatment. Thus, our report supports the notion that limited GPA itself can be associated with the development of malignancy.
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Adenocarcinoma/complicações , Carcinoma Papilar/complicações , Granulomatose com Poliangiite/complicações , Síndromes Mielodisplásicas/complicações , Neoplasias Gástricas/complicações , Neoplasias da Glândula Tireoide/complicações , Idoso , Glucocorticoides/uso terapêutico , Granulomatose com Poliangiite/tratamento farmacológico , Humanos , MasculinoRESUMO
Rheumatoid arthritis (RA) is known to be caused by autoimmune disorders and can be partially alleviated through Disease-Modifying Antirheumatic Drugs (DMARDs) therapy. However, due to significant variations in the physical environment and condition of each RA patient, the types and doses of DMARDs prescribed can differ greatly. Consequently, there is a need for a platform based on patient-derived cells to determine the effectiveness of specific DMARDs for individual patient. In this study, we established an RA three-dimensional (3D) spheroid that mimics the human body's 3D environment, enabling high-throughput assays by culturing patient-derived synovial cells on a macroscale-patterned polycaprolactone (PCL) scaffold. Fibroblast-like synoviocytes (FLSs) from patient and human umbilical vein endothelial cells (HUVECs) were co-cultured to simulate vascular delivery. Additionally, RA characteristics were identified at both the genetic and cytokine levels using real-time polymerase chain reaction (RT-qPCR) and dot blot assay. The similarities in junctions and adhesion were demonstrated in both actual RA patient tissues and 3D spheroids. The 3D RA spheroid was treated with representative DMARDs, observing changes in reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH) levels, and inflammatory cytokine responses to confirm the varying cell reactions depending on the DMARDs used. This study underscores the significance of the 3D drug screening platform, which can be applied to diverse inflammatory disease treatments as a personalized drug screening system. We anticipate that this platform will become an indispensable tool for advancing and developing personalized DMARD treatment strategies.
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PURPOSE: We investigated the efficacy and toxicity of a biweekly schedule of docetaxel and cisplatin in high-risk patients with unresectable (stages IIIB-IV) non-small cell lung cancer (NSCLC). METHODS: In this study, 48 high-risk patients with previously untreated locally advanced or metastatic NSCLC were treated with combination chemotherapy consisting of docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2); both drugs were given biweekly, on days 1 and 15, every 4 weeks in an outpatient setting. RESULTS: Complete response, partial response, and stable disease were observed in 1 (2.1%), 30 [62.5%, 95% confidence interval (CI) 47.9-77.1], and 4 (8.3%) patients. The median overall survival was 15.1 months (95% CI 11.7-18.5) and the median time to progression was 7.5 months (95% CI 6.4-8.6). The major toxicity was grade 3 anemia in 7 (14.6%) patients. Grade 3/4 neutropenia was observed in 5 (10.4%) patients. Among the nonhematologic toxicities, grade 3 infection and grade 3 diarrhea were observed in 5 (10.4%) and 4 (8.3%) patients, respectively. No treatment-related mortality was found. CONCLUSIONS: As a front-line chemotherapy for high-risk patients with unresectable NSCLC in an outpatient setting, the biweekly schedule of docetaxel and cisplatin showed feasible efficacy with acceptable hematologic toxicities, comparable to the results of previous studies of triweekly or weekly schedules. Additional large randomized studies are needed to optimize the schedule and dosage of combination therapy with docetaxel and cisplatin in high-risk patients with unresectable NSCLC.
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Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Taxoides/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/efeitos adversos , Diarreia/etiologia , Docetaxel , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/etiologia , Tomografia por Emissão de Pósitrons , Taxoides/efeitos adversos , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Introduction: The intricate connection between gut microbiota and rheumatoid arthritis (RA) pathogenesis has gained prominence, although the specific microbial species contributing to RA development remain largely unknown. Recent studies have sought to comprehensively explore alterations in the human microbiome, focusing on identifying disease-related microbial species through blood analysis. Consequently, this study aimed to identify RA-associated microbial species using a serum microbial array system and to investigate the efficacy and underlying mechanisms of potential microbial species for RA treatment. Methods: Serum immunoglobulin M levels against 384 intestinal microbial species were assessed using a microbial microarray in patients with RA and healthy individuals. We investigated the therapeutic potential of the identified microbial candidate regarding arthritis development, immune responses, gut barrier function, and gut microbiome using a collagen-induced arthritis (CIA) mouse model. Results: Our findings revealed significant alterations in antibody levels against 36 microbial species in patients with RA compared to healthy individuals. Notably, the antibody levels against Peptoniphilus gorbachii (PG) were decreased in patients with RA and exhibited an inverse correlation with RA disease activity. In vitro experiments demonstrated that PG produced acetate and butyrate, while exhibiting anti-inflammatory properties. In CIA mice, PG administration suppressed arthritis symptoms, reduced the accumulation of inflammatory monocytes in the mesenteric lymph nodes, and downregulated gene expression of pro-inflammatory cytokines in the ileum. Additionally, PG supplementation restored intestinal barrier integrity and partially resolved gut microbial dysbiosis in CIA mice. The fecal microbiota in PG-treated mice corresponded to improved intestinal barrier integrity and reduced inflammatory responses. Conclusion: This study highlights the potential of serum-based detection of anti-microbial antibodies to identify microbial targets at the species level for RA treatment. Moreover, our findings suggest that PG, identified through the microbial microarray analysis, holds therapeutic potential for RA by restoring intestinal barrier integrity and suppressing the immunologic response associated with RA.
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Artrite Experimental , Artrite Reumatoide , Firmicutes , Camundongos , Humanos , Animais , Modelos Animais de Doenças , Citocinas/metabolismoRESUMO
Interstitial lung disease (ILD) involves persistent inflammation and fibrosis, leading to respiratory failure and even death. Adult tissue-derived mesenchymal stem cells (MSCs) show potential in ILD therapeutics but obtaining an adequate quantity of cells for drug application is difficult. Daewoong Pharmaceutical's MSCs (DW-MSCs) derived from embryonic stem cells sustain a high proliferative capacity following long-term culture and expansion. The aim of this study was to investigate the therapeutic potential of DW-MSCs in experimental mouse models of ILD. DW-MSCs were expanded up to 12 passages for in vivo application in bleomycin-induced pulmonary fibrosis and collagen-induced connective tissue disease-ILD mouse models. We assessed lung inflammation and fibrosis, lung tissue immune cells, fibrosis-related gene/protein expression, apoptosis and mitochondrial function of alveolar epithelial cells, and mitochondrial transfer ability. Intravenous administration of DW-MSCs consistently improved lung fibrosis and reduced inflammatory and fibrotic markers expression in both models across various disease stages. The therapeutic effect of DW-MSCs was comparable to that following daily oral administration of nintedanib or pirfenidone. Mechanistically, DW-MSCs exhibited immunomodulatory effects by reducing the number of B cells during the early phase and increasing the ratio of Tregs to Th17 cells during the late phase of bleomycin-induced pulmonary fibrosis. Furthermore, DW-MSCs exhibited anti-apoptotic effects, increased cell viability, and improved mitochondrial respiration in alveolar epithelial cells by transferring their mitochondria to alveolar epithelial cells. Our findings indicate the strong potential of DW-MSCs in the treatment of ILD owing to their high efficacy and immunomodulatory and anti-apoptotic effects.
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Rheumatoid arthritis (RA) is a representative autoimmune disease that is primarily characterized by persistent inflammation and progressive destruction of synovial joints. RA has a complex and heterogeneous pathophysiology, involving interactions among various immune and joint stromal cells and a diverse network of cytokines and intracellular signaling pathways. With improved understanding of RA, over the past decades, therapeutic strategies have become considerably advanced and now included targeted molecular therapies, such as tumor necrosis factor inhibitors, IL-6 blockers, B-cell depletion agents, as well as inhibitors of T-cell co-stimulation and Janus kinases. However, a considerable proportion of RA patients experience refractory disease and interrupted treatment owing to the associated risk of developing serious infections and cancers. In contrast, although IL-1ß, IL-17A, and p38α play significant roles in RA pathogenesis, several drugs targeting these factors have not been approved because of their low efficacy and severe adverse effects. In this review, we provide an overview of the working mechanism, advantages, and limitations of the currently available targeted drugs for RA. Additionally, we suggest potential mechanistic causes for clinically approved and failed drugs. Thus, this review provides perspectives on approaches for basic and translational studies that hold promise for identifying future next-generation therapeutics for RA.
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OBJECTIVE: Insulin-like growth factor (IGF)-1 participates in modulating immunity and inflammation. Its bioactivity is controlled by six IGF-binding proteins (IGFBP-1 to IGFBP-6). In particular, the IGFBP-3 level is reportedly linked to the disease activity of rheumatoid arthritis (RA), consistent with our previous study. Therefore, the present study aimed to reproduce the previous results. RESULTS: The serum IGFBP-3 level was not significantly different among the three groups according to disease activity based on the DAS28-ESR/CRP (p > 0.05) but was significantly different between the low- and high-disease-activity groups based on the DAS28-CRP (p = 0.036). Meanwhile, the interleukin-6 (IL-6) level moderately correlated with DAS28-CRP (Spearman's rho = 0.583, p < 0.001).
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Artrite Reumatoide , Fator de Crescimento Insulin-Like I , Artrite Reumatoide/metabolismo , Proteína C-Reativa/metabolismo , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-6RESUMO
Lymph node fibroblastic reticular cells (LN-FRCs) provide functional structure to LNs and play important roles in interactions between T cells and antigen-presenting cells. However, the direct impact of LN-FRCs on naive CD4+ T cell differentiation has not been explored. Here, we show that T cell zone FRCs of LNs (LN-TRCs) express CD25, the α chain of the IL-2 receptor heterotrimer. Moreover, LN-TRCs trans-present IL-2 to naive CD4+ T cells through CD25, thereby facilitating early IL-2-mediated signaling. CD25-deficient LN-TRCs exhibit attenuated STAT5 phosphorylation in naive CD4+ T cells during T cell differentiation, promoting T helper 17 (Th17) cell differentiation and Th17 response-related gene expression. In experimental autoimmune disease models, disease severity was elevated in mice lacking CD25 in LN-TRCs. Therefore, our results suggest that CD25 expression on LN-TRCs regulates CD4+ T cell differentiation by modulating early IL-2 signaling of neighboring, naive CD4+ T cells, influencing the overall properties of immune responses.
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Linfócitos T CD4-Positivos , Subunidade alfa de Receptor de Interleucina-2 , Interleucina-2 , Animais , Diferenciação Celular , Fibroblastos/metabolismo , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfonodos , CamundongosRESUMO
This study aimed to identify differences in clinical and dietary characteristics, serum adipokine levels, and metabolomic profiles between early- and late-onset gout. Eighty-three men with gout were divided into an early-onset group (n = 38, aged < 40 years) and a late-onset group (n = 45, aged ≥ 40 years). Dietary and clinical information was obtained at baseline. Serum adipokines, including adiponectin, resistin, leptin, and plasminogen activator inhibitor-1 (PAI-1), were quantified by a Luminex multiplex immunoassay. Metabolite expression levels in plasma were measured in 22 representative samples using metabolomics analysis based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Average body mass index, rate of consumption of sugar-sweetened beverages, and serum uric acid levels were significantly higher in the early-onset group (p < 0.05), as was the PAI-I concentration (105.01 ± 42.45 ng/mL vs. 83.76 ± 31.16 ng/mL, p = 0.013). Changes in levels of metabolites mostly involved those related to lipid metabolism. In the early-onset group, acylcarnitine analog and propylparaben levels were downregulated and negatively correlated with the PAI-1 concentration whereas LPC (22:6) and LPC (18:0) levels were upregulated and positively correlated with the PAI-1 concentration. Dietary and clinical features, serum adipokine concentrations, and metabolites differed according to whether the gout is early-onset or late-onset. The mechanisms of gout may differ between these groups and require different treatment approaches.
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Socioeconomic status (SES), which takes into account household income and education level, is an important factor in the role of muscle strength as a discriminator of sarcopenia. Although the benefits of exercise on muscle strength are well recognized, its influence on people of different SES has not been fully elucidated, informing the aim of this study. A total of 6081 subjects, for which we had complete data on measurements of handgrip strength (HGS) and other relevant variables, were included from the Korea National Health and Nutrition Examination Surveys (KNHANES) VII-3. A multivariable analysis showed that people with a low household income (odds ratio (OR) 1.637, p = 0.005) and low education status (OR 2.351, p < 0.001) had a poor HGS compared to those with a high SES, and that the difference in HGS made by muscle exercise was greater for people with a low household income (OR 7.082 vs. 3.619, p < 0.001) and low education status (OR 14.711 vs. 6.383, p < 0.001). Three-step logistic regression analysis showed that muscle exercise mediated the relationship between muscle strength and low household income (OR from 1.772 to 1.736, z = 2.373, p = 0.017) and low education level (OR from 2.368 to 2.309, z = 2.489, p = 0.012). This study confirmed that exercise improves the negative effect of SES on muscle strength, suggesting the greater importance of muscle exercise for people with a low SES.
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Histamine releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses, but the role of HRF/TCTP in rheumatoid arthritis (RA) remains undefined. In this study, we explored the pathogenic significance of HRF/TCTP and evaluated the therapeutic effects of HRF/TCTP blockade in RA. HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine the experimental phenotypes of RA. HRF/TCTP levels in the sera of RA patients were measured and compared to those from patients with osteoarthritis (OA), ankylosing spondylitis, Behçet's disease, and healthy controls. HRF/TCTP expression was also assessed in the synovium and fibroblast-like synoviocytes (FLSs) obtained from RA or OA patients. Finally, we assessed the effects of HRF/TCTP and dimerized HRF/TCTP-binding peptide-2 (dTBP2), an HRF/TCTP inhibitor, in RA-FLSs and CIA mice. Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels in the sera, synovial fluid, synovium, and FLSs were higher in patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with RA disease activity. The tumor-like aggressiveness of RA-FLSs was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice and had no detrimental effects in a murine tuberculosis model. Our results indicate that HRF/TCTP is a novel biomarker and therapeutic target for the diagnosis and treatment of RA.