RESUMO
Smoke inhalation injury (SII) is the leading cause of death in fire burn patients. The inflammatory response induced by smoke inhalation is a significant factor in the development of acute lung injury or acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) can alleviate various inflammatory diseases by regulating the polarization of macrophages from the M1 to the M2 phenotype. Moreover, MSCs can facilitate the inflammatory response by regulating Th17/Treg homeostasis. However, little is known about the associations among MSCs, M1/M2 macrophages and Th17/Treg homeostasis. Therefore, the purpose of this study was to evaluate whether MSCs affect subsequent Th17/Treg differentiation and immune homeostasis by regulating M1/M2 polarization in SII. Our results showed that bone marrow mesenchymal stem cells (BMSCs) ameliorated lung inflammatory injury and fibrosis after SII by affecting the polarization of alveolar macrophages (AMs) from the M1 to the M2 phenotype. Moreover, BMSCs maintain Th17/Treg immune homeostasis by increasing the proportion of Treg cells and decreasing the proportion of Th17 cells. In vitro, we further demonstrated that BMSCs promoted the polarization of AMs from the M1 to the M2 phenotype and decreased IL-23 levels. Reduced IL-23 decreased Th17 differentiation and promoted Th17/Treg balance. Therefore, BMSCs ameliorate the inflammatory response and lung damage after SII through regulating M1/M2 polarization and subsequent Th17/Treg immune homeostasis, which are linked to alveolar macrophage-derived IL-23. These findings provide novel insight into how BMSCs regulate the M1/M2-Th17/Treg immune homeostasis axis and provide new therapeutic targets for more effective control of the inflammatory response after SII.
RESUMO
Graves' disease (GD) is an autoimmune disease and the most common cause of hyperthyroidism. While the phosphotyrosine phosphatase non-receptor type 22 (PTPN22) variant is associated with GD susceptibility, its precise role and mechanism in GD remain unclear. To investigate this, we induced GD in mice using Ad-TSHR289 and isolated CD4+ T cells from spleen tissues. We conducted a series of experiments, including hematoxylin-eosin staining, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, flow cytometry, immunofluorescence (IF), reverse transcription quantitative PCR (RT-qPCR), and western blotting. PTPN22 expression was found to be downregulated in GD mice. Overexpression of PTPN22 ameliorated pathological damage and increased serum levels of T4 and thyroid stimulating hormone receptor antibody (TRAb), as well as the ratio of thyroid weight to body weight in GD mice. Furthermore, GD mice exhibited elevated levels of CD4+ and IL-17+ T cells, an increased Th17/Treg ratio, and upregulation of IL-17A mRNA expression. Conversely, there was a decrease in Foxp3+ T cells and transcriptional levels of Foxp3, which were reversed by PTPN22 overexpression. In vitro experiments showed that PTPN22 overexpression in CD4+ T cells from spleen tissues of GD mice enhanced Foxp3 expression while reducing IL-17A expression. Mechanistically, PTPN22 overexpression led to decreased levels of phosphorylated Lck (p-Lck), Lck, phosphorylated Fyn (p-Fyn), Fyn, phosphorylated Zap70 (p-Zap70), and Zap70 in both in vivo and in vitro GD models. In summary, PTPN22 can alleviate thyroid dysfunction in GD by modulating Th17/Treg balance through the downregulation of the Lck/Zap70 signaling axis.
RESUMO
SMARCA5, a protein in the SWI/SNF family, has been previously implicated in the development of ulcerative colitis (UC) through methylation. However, the specific molecular mechanisms by which SMARCA5 contributes to colonic inflammation and the imbalance between Th17 and Treg cells remain unclear. This study was designed to explore these molecular mechanisms. A UC mouse model was established using dextran sulfate sodium induction, followed by measurements of mouse weight, disease activity index (DAI) score, colon length, pathological changes in the colon, and FITC-dextran concentration. The levels of IL-17a, IFN-γ, IL-6, TNF-α, TGF-ß, and IL-10 were measured, along with the protein expression of ZO-1 and Occludin. Flow cytometry was used to assess the presence of IL-17 + CD4 + (Th17 +) cells and FOXP3 + CD25 + CD4 + (Treg +) cells in the spleen and mesenteric lymph nodes of UC mice. We observed that SMARCA5 and RNF180 were increased, while ALKBH5 was downregulated in UC mouse colon tissue. SMARCA5 or RNF180 knockdown or ALKBH5 overexpression ameliorated the colon inflammation and Th17/Treg cell imbalance in UC mice, shown by increased body weight, colon length, FOXP3 + CD25 + CD4 + T cells, and the levels of ZO-1, Occludin, TGF-ß, IL-10, and FOXP3. It decreased DAI scores, IL-17 + CD4 + T cells, and levels of IL-17a, IFN-γ, IL-6, TNF-α, and ROR-γt. ALKBH5 inhibited SMARCA5 expression via m6A modification, while RNF180 reduced ALKBH5 expression via ubiquitination. Our findings indicate that RNF180 aggravated the colon inflammation and Th17/Treg cell imbalance in UC mice by regulating the ALKBH5/SMARCA5 axis.
Assuntos
Colite Ulcerativa , Linfócitos T Reguladores , Células Th17 , Ubiquitina-Proteína Ligases , Animais , Células Th17/imunologia , Células Th17/metabolismo , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Camundongos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Masculino , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Inflamação/patologia , Inflamação/imunologia , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: Respiratory viruses are increasingly detected in children with community-acquired pneumonia. Further strategies to limit antibiotic use in children with viral pneumonia are warranted. AIM: To explore clinical efficacy of budesonide/formoterol inhalation powder for viral pneumonia in children and its impact on cellular immunity and inflammatory factor production. METHODS: A total of 60 children with viral pneumonia were recruited: 30 receiving budesonide/formoterol inhalation powder and 30 conventional symptomatic treatment. Outcome measures included peripheral blood levels of inflammatory cytokines, CD4+, CD8+, Th1, Th2, Th17 and Treg, clinical efficacy, and incidence of adverse reactions. RESULTS: Compared with the control group, the observation group showed a significant reduction in interleukin-6 and high-sensitivity C-reactive protein levels after treatment. Compared with the control group, the observation group showed a significant increase in CD4+/CD8+ and Th1/Th2 levels, and a decrease in Th17/Treg levels after treatment. The total effective rates in the observation group and the control group were 93.75% and 85.00%, respectively, which was a significant difference (P = 0.003). CONCLUSION: Budesonide/formoterol inhalation powder significantly improved therapeutic efficacy for viral pneumonia in children. The mechanism of action may be related to downregulation of the inflammatory response and improved cellular immune function.
RESUMO
Purpose: The objective of this study was to investigate the effects of agrimonolide (AM) on mice with dextran sulfate sodium (DSS)-induced colitis and elucidate its protective mechanisms. Methods: A 3 % DSS solution was used to induce colitis, and intragastric administration of AM at doses of 25 and 50 mg/kg was performed. A comprehensive assessment was conducted to evaluate inflammatory responses and mucosal integrity in the colon. Inflammatory factors were quantified using enzyme-linked immunosorbent assay (ELISA). The proportions of T helper cell 17 (Th17) and regulatory T cells (Treg) cells in mesenteric lymph nodes (MLNs) was analyzed through RT-qPCR and flow cytometry. Proteins associated with the Notch and JAK2/STAT3 pathways were examined via RT-qPCR, western blotting, and immunofluorescence. Additionally, the impact of AM on Treg and Th17 cell differentiation was investigated in vitro. Results: Pre-treatment with AM significantly alleviated colon inflammation in mice, as evidenced by reduced body weight loss, shorter colon length, lower disease activity index (DAI) score, and decreased myeloperoxidase (MPO) content. Notably, AM pre-treatment attenuated the production of pro-inflammatory cytokines, including interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6, in mice with DSS-induced colitis. Additionally, AM pre-treatment significantly enhanced the expression of tight junction proteins (Occludin and ZO-1), thereby preserving gut barrier function. Moreover, we observed that AM administration decreased the ratio of Th17 cells while increasing the frequency of colonic Treg cells, thus modulating the Th17/Treg balance both in vivo and in vitro. Furthermore, in the AM-treated group, the expression of Notch-1, Jagged1, delta like 4 (DLL4), phospho-janus kinases 2 (p-JAK2)/JAK2, and p-signal transducer and activator of transcription 3 (STAT3)/STAT3 in colonic tissue was reduced compared to the DSS group. Remarkably, the therapeutic effects of AM in colitis mice were blocked by a Notch activator. Conclusion: These findings underscore the effectiveness of AM in alleviating symptoms and pathological damage in DSS-induced colitis mice by rebalancing Th17/Treg cell homeostasis through modulation of the Notch and JAK2/STAT3 signaling pathways. These insights into AM's mechanisms of action offer potential avenues for novel therapeutic strategies.
RESUMO
Inflammatory Bowel Disease (IBD) is a chronic condition whose incidence has been rising globally. Synbiotic (SYN) is an effective means of preventing IBD. This study investigated the preventive effects and potential biological mechanisms of SYN (Bifidobacterium longum, Lactobacillus acidophilus, and sea buckthorn polysaccharides) on DSS-induced colitis in mice. The results indicated that dietary supplementation with SYN has a significant improvement effect on DSS mice. SYN ameliorated disease activity index (DAI), colon length, and intestinal barrier permeability in mice. In addition, RT-qPCR results indicated that after SYN intervention, the expression levels of pro-inflammatory factors (IL-6, IL-1ß, TNF-α, and IL-17F) and transcription factor RORγt secreted by Th17 cells were significantly reduced, and the expression levels of anti-inflammatory factors (IL-10 and TGF-ß) and transcription factor Foxp3 secreted by Treg cells were robustly increased. 16S rDNA sequencing analysis revealed that key intestinal microbiota related to Th17/Treg balance (Ligilactobacillus, Lactobacillus, Bacteroides, and Akkermansia) was significantly enriched. At the same time, a significant increase in microbial metabolites SCFAs and BAs was observed. We speculate that SYN may regulate the Th17/Treg balance by restructuring the structure and composition of the intestinal microbiota, thereby mitigating DSS-induced colitis.
Assuntos
Colite , Sulfato de Dextrana , Microbioma Gastrointestinal , Hippophae , Polissacarídeos , Simbióticos , Linfócitos T Reguladores , Células Th17 , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Colite/induzido quimicamente , Colite/imunologia , Colite/metabolismo , Camundongos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Polissacarídeos/farmacologia , Hippophae/química , Ácidos Graxos Voláteis/metabolismo , Homeostase/efeitos dos fármacos , Masculino , Citocinas/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: The development of gut-liver axis metabolic immune crosstalk is intimately associated with intestinal barrier disorder, intestinal SCFAs-Th17/Treg immunological imbalance, and disorders of the gut microbiota. Prior research has discovered that Dendrobium officinale National Herbal Drink (NHD), a traditional Chinese medicine drink with enhanced immunity, may enhance the immunological response in animals with impaired immune systems brought on by cyclophosphamide by repairing intestinal barrier function and controlling turbulence in the gut microbiota. However, whether NHD can further improve the gut-liver axis metabolic immune crosstalk and its related mechanisms need to be systematically studied. OBJECTIVES: The purpose of this study is to clarify the function and mechanism of NHD in enhancing the gut-liver axis metabolic immunological crosstalk brought on by excessive alcohol intake. METHODS: In this work, we set up a mouse model to analyze the metabolic and immunological crosstalk involving the gut-liver axis across 7 weeks of continuous, excessive drinking. At the same time, high and low doses (20,10 ml/kg) of NHD were given by gavage. The effect of NHD on improving the metabolism of gut-liver axis was evaluated by blood lipid, liver lipid deposition, liver function and intestinal pathophysiology. By measuring serum immunological indices, intestinal barrier, and intestinal immune barrier, the impact of NHD on enhancing immune and intestinal barrier function was assessed. Furthermore, immunohistochemistry, immunofluorescence, 16S rRNA, Western blot, q-PCR and other methods were used to detect gut microbiota, SCFAs-GPR41/43 pathway, intestinal Th17/Treg immune cells and PPAR-α-NPC1L1/SREBP1 pathway to elucidate the mechanism by which NHD enhances the gut-liver axis' metabolic immune crosstalk. RESULTS: Our study demonstrated that NHD has the potential to improve the pathophysiological damage caused by gut-liver axis in model mice. NHD also ameliorated the disorder of lipid metabolism. In addition, it regulated the levels of peripheral blood T cell immunity and serum immune factors. And NHD can restore intestinal mechanical and immune barrier damage. NHD has a favorable impact on the quantity of beneficial bacteria, including uncultured_bacterium_g__norank_f__muribaculacea and uncultured_bacterium_g__Turicibacter. Additionally, it raised the model mice's levels of SCFAs (n-butyric acid, isovaleric acid, etc.). This resulted in the promotion of intestinal GPR41/43-ERK1/2 expression and the reshaping of intestinal CD4+T cell Th17/Treg homeostasis. As a consequence, colon IL-22 and IL-10 levels increased, while colon IL-17A levels decreased. Lastly, NHD raised the amount of intestinal IAP/LPS, regulated the development of PPAR-α-NPC1L1/SREBP1 pathway in gut-liver axis, and improve lipid metabolism disorder. CONCLUSIONS: Our study found that NHD can improve the gut-liver axis metabolic immune crosstalk in model mice caused by excessive drinking. The mechanism might be connected to how NHD controls gut microbiota disorders in model mice, the activation of intestinal SCFAs-GPR41/43 pathway, the remodeling of Th17/Treg immune homeostasis of intestinal CD4+T cells, the improvement of IAP/LPS abnormality, and further mediating the PPAR-α-NPC1L1/SREBP1 pathway of lipid metabolism in gut-liver axis.
Assuntos
Dendrobium , Medicamentos de Ervas Chinesas , Ácidos Graxos Voláteis , Microbioma Gastrointestinal , Fígado , Linfócitos T Reguladores , Células Th17 , Animais , Dendrobium/química , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Medicamentos de Ervas Chinesas/farmacologia , Ácidos Graxos Voláteis/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Disruption of the extracellular matrix and dysregulation of the balance between Th17 and regulatory T cells are recognized as risk factors for recurrent spontaneous abortion (RSA). However, the interaction between matrix components and the Th17/Treg axis remains poorly elucidated. The result of this study revealed that the absence of type I collagen in the decidua is linked to Th17/Treg imbalance in RSA. Furthermore, we discovered that biomaterial recombinant humanized type I collagen (rhCOLI) promoted T cell differentiation into Tregs by inhibition the Notch1/Hes1 signaling pathway and enhanced the immunosuppressive function of Tregs, as indicated by increased secretion level of IL-10 and TGF-ß. Importantly, this study is the first to demonstrate that rhCOLI can modulate the Th17/Treg imbalance, reduce embryo resorption rates, reshape the immune microenvironment at the maternal-fetal interface, and improve fertility in an RSA mouse model. Collectively, these findings suggest that type I collagen deficiency may contribute to, rather than result from, RSA, and propose a potential intervention for RSA using rhCOLI.
Assuntos
Colágeno Tipo I , Decídua , Proteínas Recombinantes , Linfócitos T Reguladores , Células Th17 , Feminino , Colágeno Tipo I/metabolismo , Animais , Células Th17/imunologia , Gravidez , Decídua/imunologia , Decídua/metabolismo , Camundongos , Humanos , Linfócitos T Reguladores/imunologia , Proteínas Recombinantes/farmacologia , Aborto Habitual/imunologia , Diferenciação Celular/efeitos dos fármacosRESUMO
Our previous study found that early weaning is associated with decreased growth performance, intestinal barrier impairment, and an imbalance in Th17/Treg in pigeon squabs. Chitosan oligosaccharides (COS) has been substantiated to regulate gut microbiota and restore Th17/Treg equilibrium in mammals, thereby ameliorating growth performance. However, the potential effects of COS in altricial birds remain unclear. Three hundred healthy 7-day-old American king pigeon squabs were selected with similar body weights and randomly divided into 5 groups. The 5 treatment groups were as follows: the control group (CON), fed with artificial pigeon milk; 4 supplementation groups, fed with artificial pigeon milk +100 (COS1), 150 (COS2), 200 (COS3), and 250 (COS4) mg/kg COS, respectively. Results showed that dietary supplementation of COS significantly enhanced the growth performance of weaned squabs. Compared to the CON group, the COS groups exhibited increased villus length and villus area in the jejunum and ileum, accompanied by improvements in morphological structure and mucosal permeability. COS was found to reduce the levels of Th17-associated cytokines and increase the levels of Treg-associated cytokines. COS downregulated the expression of retinoic acid receptor-related orphan receptor C (RORC), a key transcription factor of Th17 cells, while upregulated the expression of Forkhead box protein P3 (FOXP3), a key transcription factor of Treg cells. Dietary COS supplementation increased gut bacterial diversity, altered the relative abundance of several bacteria taxa and enhanced the concentration of short-chain fatty acids (SCFA). Correlation analysis demonstrated a close association between gut microbiota, SCFAs, and indicators related to the Th17/Treg balance. Moreover, we found that SCFAs correlated more strongly with Th17/Treg-related indexes than gut microbiota. These results demonstrated that COS could relieve early weaning stress in pigeon squabs and the optimal dosage of dietary COS supplementation was suggested to be 200 mg/kg. In addition, COS had a protective effect on maintaining intestinal immune balance by modulating microbiota and Th17/Treg related signaling pathways, in which SCFAs might play a crucial role as messengers.
RESUMO
Chlamydia psittaci pneumonia (CPP) is a lung disease caused by the infection with the Chla-mydia psittaci bacterium, which can lead to severe acute respiratory distress syndrome and systemic symptoms. This study explored the specific mechanisms underlying the impact of reactive oxygen species (ROS) on the Th17/Treg balance in CPP. The levels of ROS and the differentiation ratio of Th17/Treg in the peripheral blood of healthy individuals and CPP patients were measured using ELISA and flow cytometry, respectively. The association between the ROS levels and Th17/Treg was assessed using Pearson correlation analysis. The ROS levels and the Th17/Treg ratio were measured in CD4+ T cells following H2O2 treatment and NLRP3 inhibition. The effects of H2O2 treatment and NLRP3 inhibition on the NLRP3/IL-1ß/caspase-1 pathway were observed using immunoblotting. Compared to the healthy group, the CPP group exhibited increased levels of ROS in the peripheral blood, an elevated ratio of Th17 differentiation, and a decreased ratio of Treg differentiation. ROS levels were positively correlated with the Th17 cell proportion but negatively correlated with the Treg cell proportion. The ROS levels and NLRP3/IL-1ß/caspase-1 expression were up-regulated in CD4+ T cells after H2O2 treatment. Furthermore, there was an increase in Th17 differentiation and a decrease in Treg differentiation. Conversely, the NLRP3/IL-1ß/caspase-1 pathway inhibition reversed the effects of H2O2 treatment, with no significant change in the ROS levels. ROS regulates the Th17/Treg balance in CPP, possibly through the NLRP3/IL-1ß/caspase-1 pathway. This study provides a new perspective on the development of immunotherapy for CPP.
Assuntos
Caspase 1 , Diferenciação Celular , Chlamydophila psittaci , Interleucina-1beta , Proteína 3 que Contém Domínio de Pirina da Família NLR , Espécies Reativas de Oxigênio , Linfócitos T Reguladores , Células Th17 , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T Reguladores/imunologia , Caspase 1/metabolismo , Diferenciação Celular/efeitos dos fármacos , Interleucina-1beta/metabolismo , Transdução de Sinais , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Peróxido de Hidrogênio/metabolismo , PsitacoseRESUMO
BACKGROUND: Iguratimod (IGU) is widely used in clinical practice due to its stable anti-inflammatory effects. Our previous studies have confirmed that the proportion of Th17/Treg balance in patients taking IGU altered significantly. This study aims to explore the role of IGU in antibody-mediated rejection (ABMR) and its potential mechanisms. METHODS: We conducted bioinformatics analysis of sequencing data from the GEO database to analyze the abundance of immune cell infiltration in transplanted kidney tissues. In vivo, IGU was intervened in a mice secondary skin transplantation model and a mice kidney transplantation ABMR model, and histological morphology of the grafts were examined by pathological staining, while relevant indicators were determined through qRT-PCR, immunohistochemistry, and enzyme-linked immunosorbent assay, observed T cell differentiation by flow cytometry, and preliminarily assessed the immunosuppressive effect of IGU. In vitro, we established Th17 and Treg cell induction and stimulation differentiation culture systems and added IGU for intervention to explore its effects on their differentiation. RESULTS: Through bioinformatics analysis, we found that Th17 and Treg may play important roles in the occurrence and development of ABMR. In vivo, we found that IGU could effectively reduce the damage caused by ABMR to the grafts, alleviate the infiltration of inflammatory cells in the graft tissues, and reduce the deposition of C4d in the grafts. Moreover, it is also found that IGU regulated the differentiation of Th17 and Treg cells in the spleen and peripheral blood and reduced the expression of IL-17A in the grafts and serum. In addition, same changes were observed in the induction and differentiation culture system of Th17 and Treg cells in vitro after the addition of IGU. CONCLUSION: IGU can inhibit the progression of ABMR by regulating the differentiation of Th17 and Treg cells, providing novel insights for optimizing clinical immunosuppressive treatment regimens.
Assuntos
Cromonas , Rejeição de Enxerto , Transplante de Rim , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores , Células Th17 , Animais , Células Th17/imunologia , Linfócitos T Reguladores/imunologia , Rejeição de Enxerto/imunologia , Camundongos , Cromonas/farmacologia , Masculino , Imunossupressores/uso terapêutico , Humanos , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Células Cultivadas , SulfonamidasRESUMO
Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy. In this study, we investigated the potential protective effect of Lactobacillus rhamnosus GG (LGG) on radiation-induced intestinal injury and its underlying mechanisms. Mice were assigned to a control group, a 10â¯Gy total abdominal irradiation (TAI) group, or a group pretreated with 108 CFU LGG for three days before TAI. Small intestine and gut microbiota were analyzed 3.5 days post-exposure. LGG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the inflammatory cGAS/STING pathway. Furthermore, LGG reduced M1 proinflammatory macrophage and CD8+ T cell infiltration, restoring the balance between Th17 and Treg cells in the inflamed jejunum. LGG also partially restored the gut microbiota. These findings suggest the possible therapeutic radioprotective effect of probiotics LGG in alleviating radiation-induced intestinal injury by maintaining immune homeostasis and reshaping gut microbiota.
Assuntos
Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Camundongos Endogâmicos C57BL , Probióticos , Animais , Microbioma Gastrointestinal/efeitos da radiação , Camundongos , Probióticos/administração & dosagem , Lesões por Radiação/imunologia , Macrófagos/imunologia , Intestinos/microbiologia , Intestinos/efeitos da radiação , Intestinos/imunologia , Dano ao DNA , Linfócitos T CD8-Positivos/imunologia , Proteínas de Membrana/metabolismo , Linfócitos T Reguladores/imunologia , Masculino , Células Th17/imunologia , Jejuno/efeitos da radiação , Jejuno/imunologia , Jejuno/microbiologia , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Lesões Experimentais por Radiação/imunologia , Lesões Experimentais por Radiação/prevenção & controle , NucleotidiltransferasesRESUMO
BACKGROUND: Severe acute pancreatitis (SAP) is associated with tremendous systemic inflammation, T-helper 17 (Th17) cells, and regulatory T (Treg) cells play an essential role in the inflammatory responses. Meanwhile, soluble fibrinogen-like protein 2 (Sfgl2) is a critical immunosuppressive effector cytokine of Treg cells and modulates immune responses. However, the impact of SAP induction on Sfgl2 expression and the role of Sfgl2 in immunomodulation under SAP conditions are largely unknown. METHODS: A taurocholate-induced mouse SAP model was established. The ratios of CD4+CD25+Foxp3+ Treg cells or CD4+IL-17+ Th17 cells in blood and pancreatic tissues as well as surface expression of CD80, CD86, and major histocompatibility complex class II (MHC-II) were determined by flow cytometry. Gene mRNA expression was determined by qPCR. Serum amylase and soluble factors were quantitated by commercial kits. Bone marrow-derived dendritic cells (DCs) were generated, and NF-κB/p65 translocation was measured by immunofluorescence staining. RESULTS: SAP induction in mice decreased the Th17/Treg ratio in the pancreatic tissue and increased the Th17/Treg ratio in the peripheral blood. In addition, SAP was associated with a reduced level of Sfgl2 in the pancreatic tissue and blood: higher levels of serum IL-17, IL-2, IFN-α, and TNF-α, and lower levels of serum IL-4 and IL-10. Furthermore, the SAP-induced reduction in Sfgl2 expression was accompanied by dysregulated maturation of bone marrow-derived DCs. CONCLUSIONS: SAP causes reduced Sfgl2 expression and Th17/Treg imbalance, thus providing critical insights for the development of Sfgl2- and Th17/Treg balance-targeted immunotherapies for patients with SAP.
Assuntos
Modelos Animais de Doenças , Fibrinogênio , Pancreatite , Linfócitos T Reguladores , Ácido Taurocólico , Células Th17 , Animais , Células Th17/imunologia , Linfócitos T Reguladores/imunologia , Pancreatite/imunologia , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Camundongos , Fibrinogênio/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Regulação para Baixo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Doença Aguda , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/metabolismoRESUMO
BACKGROUND: The incidence rate of allergic rhinitis (AR) is on the rise, which seriously affects the quality of life, work efficiency, mental state of patients, and sleeping in AR sleep. This experiment aimed to investigate the changes in Treg/Th17 cells in the nasal mucosa of an AR mouse model and the intervention effect of an Anti-IL-17 antibody. METHODS: A mouse model of AR was induced by intraperitoneal ovalbumin (OVA) injection for sensitization and stimulation with nasal drops. The times of rubbing, sneezing, and symptomatology scores were counted and analyzed. Pathological damage to the nasal mucosa was observed by Hematoxylin-Eosin (HE) staining. Peripheral blood CD4+CD25+CD127- Treg cell levels and the content of Th17 cells were measured by flow cytometry (FCM). ELISA kits were used to detect the levels of relevant cytokines (IL-10 and TGF-ß1) secreted by Treg cells. The intervention effect of Anti-IL-17 antibody was observed by giving Anti-IL-17 antibody treatment. RESULTS: The times of rubbing, sneezing, and symptomatology scores were significantly higher in mice in the OVA group than in the Control group (p < 0.001). The percentage of CD4+CD25+CD127- Treg cells in CD4+CD25+ T cells (p < 0.05) and the levels of IL-10 (p < 0.001) and TGF-ß1 (p < 0.001) were significantly decreased. After OVA induction, the continuity of the nasal mucosa of mice was interrupted, the percentage of Th17 cells, IL-17, and IL-4 levels were increased, and IFN-γ levels were significantly reduced (p < 0.001). And protein expression of RORγt was significantly upregulated (p < 0.001). In addition, all of these results were reversed by Anti-IL-17 antibody treatment, significantly improving AR-related symptoms (p < 0.05). CONCLUSION: Anti-IL-17 antibodies may regulate the body's immune response by promoting CD4+CD25+CD127- Treg cell differentiation, thereby ameliorating the symptoms associated with AR.
Assuntos
Modelos Animais de Doenças , Interleucina-17 , Camundongos Endogâmicos BALB C , Mucosa Nasal , Rinite Alérgica , Linfócitos T Reguladores , Células Th17 , Animais , Linfócitos T Reguladores/imunologia , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Rinite Alérgica/imunologia , Rinite Alérgica/patologia , Rinite Alérgica/sangue , Células Th17/imunologia , Camundongos , Interleucina-17/imunologia , Interleucina-17/metabolismo , Feminino , Ovalbumina/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/imunologia , Interleucina-10/imunologia , Interleucina-10/metabolismo , Anticorpos/imunologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Da-Jian-Zhong decoction (DJZD) is a herbal formula clinically used for abdominal pain and diarrhea induced by spleen-Yang deficiency syndrome. Recently, treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) with DJZD has received increasing attention, but the underlying mechanism of action remains elusive. AIM OF THE STUDY: We aimed to evaluate the therapeutic effect of DJZD on IBS-D rats and to elucidate the underlying mechanisms. MATERIALS AND METHODS: An IBS-D rats model was constructed using a two-factor superposition method of neonatal maternal separation and Senna folium aqueous extract lavage. Moreover, the effect of DJZD was evaluated based on the body weight, rectal temperature, abdominal withdrawal reflex (AWR), and Bristol stool scale score (BSS). The factors that regulate the DJZD effects on IBS-D were estimated using whole microbial genome, transcriptome sequencing (RNA-Seq), flow cytometry, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) analyses. RESULTS: We found that DJZD alleviated the symptoms of IBS-D rats, with the low-dose (2.4 g/kg) as the better ones, as shown by the higher body weight and lower AWR score and BSS. At the phylum level, the relative abundance of Bacteroidetes was obviously increased, and at the genus level, Lactobacillus and Parabacteroides were increased, while that of Firmicutes_bacterium_424 and Ruminococcus gnavus was decreased in DJZD group. Furthermore, the significantly enriched GO terms after treatment with DJZD mainly included the immune response, positive regulation of activated T cell proliferation, and positive regulation of interleukin-17 (IL-17) production. Importantly, flow cytometry analysis further revealed that the T helper cell type 17/regulatory T cell (Th17/Treg) balance contributed to the DJZD-induced alleviation of IBS-D symptoms, as DJZD downregulated Th17/Treg ratio and Th17 cell-related cytokines IL-17 and IL-6 levels in the colon. CONCLUSIONS: These results demonstrated that DJZD has a good therapeutic effect on IBS-D rats, probably by maintaining the homeostasis of gut microbiota and regulating Th17/Treg balance and its related inflammatory factors.
Assuntos
Diarreia , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Síndrome do Intestino Irritável , Ratos Sprague-Dawley , Linfócitos T Reguladores , Células Th17 , Animais , Síndrome do Intestino Irritável/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Diarreia/tratamento farmacológico , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Masculino , Linfócitos T Reguladores/efeitos dos fármacos , Ratos , Modelos Animais de Doenças , FemininoRESUMO
Pyruvate kinase isoform 2 (PKM2) is closely related to the regulation of Th17/Treg balance, which is considered to be an effective strategy for UC therapy. Parthenolide (PTL), a natural product, only possesses moderate PKM2-activating activity. Thus, five series of PTL derivatives are designed and synthesized to improve PKM2-activated activities and anti-UC abilities. Through detailed structure optimization, B4 demonstrates potent T-cell anti-proliferation activity (IC50 = 0.43 µM) and excellent PKM2-activated ability (AC50 = 0.144 µM). Subsequently, through mass spectrometry analysis, B4 is identified to interact with Cys423 of PKM2 via covalent-bond. Molecular docking and molecular dynamic simulation results reveal that the trifluoromethoxy of B4 forms a stronger hydrophobic interaction with Ala401, Pro402, and Ile403. In addition, B4 has a significant effect only on Th17 cell differentiation, thereby regulating the Th17/Treg balance. The effect of B4 on Th17/Treg imbalance can be attributed to inhibition of PKM2 dimer translocation and suppression of glucose metabolism. Finally, B4 can notably ameliorate the symptoms of dextran sulfate sodium (DSS)-induced colitis in mouse model in vivo. Thus, B4 is confirmed as a potent PKM2 activator, and has the potential to develop as a novel anti-UC agent.
Assuntos
Colite Ulcerativa , Desenho de Fármacos , Lactonas , Piruvato Quinase , Sesquiterpenos , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Sesquiterpenos/síntese química , Animais , Camundongos , Piruvato Quinase/metabolismo , Piruvato Quinase/antagonistas & inibidores , Lactonas/farmacologia , Lactonas/química , Lactonas/síntese química , Relação Estrutura-Atividade , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/induzido quimicamente , Humanos , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Relação Dose-Resposta a Droga , Masculino , Sulfato de Dextrana , Simulação de Acoplamento Molecular , Hormônios Tireóideos/metabolismo , Células Th17/efeitos dos fármacos , Proteínas de Ligação a Hormônio da TireoideRESUMO
Intestinal damage and secondary bacterial translocation are caused by the inflammatory response induced by sepsis. Tongfu Lifei (TLF) decoction has a protective effect on sepsis-related gastrointestinal function injury. However, the relation between gut microbiota, immune barrier, and sepsis under the treatment of TLF have not been well clarified yet. Here, rats were subjected to cecal ligation and puncture (CLP) to create a sepsis model. Subsequently, the TLF decoction was given to CLP rats by gavage, fecal microbiota transplantation (FMT), and antibiotic were used as positive control. TLF suppressed the inflammatory response and improved the pathological changes in the intestines of CLP rats. Besides, TLF promoted the balance of the percentage of the Th17 and Treg cells. Intestinal barrier function was also improved by TLF through enhancing ZO-1, and Occludin and Claudin 1 expression, preventing the secondary translocation of other gut microbiota. TLF dramatically boosted the gut microbiota's alpha- and beta-diversity in CLP rats. Moreover, it increased the relative abundance of anti-inflammatory gut microbiota and changed the progress of the glucose metabolism. In short, TLF regulated the gut microbiota to balance the ratio of Th17/Treg cells, reducing the inflammation in serum and intestinal mucosal injury in rats.
Assuntos
Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Mucosa Intestinal , Sepse , Linfócitos T Reguladores , Células Th17 , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Sepse/imunologia , Sepse/tratamento farmacológico , Sepse/complicações , Células Th17/imunologia , Células Th17/efeitos dos fármacos , Ratos , Medicamentos de Ervas Chinesas/farmacologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/microbiologia , Masculino , Ratos Sprague-DawleyRESUMO
Periodontitis is a multifactorial inflammatory disease characterized by severe alveolar bone damage and attachment loss. The imbalance of T help 17 (Th17) / regulatory T cells (Treg) induces excessive interleukin (IL)-17, which leads to alveolar bone damage and aggravates the development of periodontitis. Therefore, we proposed a therapeutic strategy to restore Th17/Treg homeostasis by interfering reactive oxygen species (ROS)-macrophage polarization cascade using active targeting microemulsions-based thermosensitive hydrogel. Folic acid-modified quercetin-loaded microemulsions (FA-Qu-MEs) were dispersed in poloxamer 407 and poly(N-isopropylacrylamide) matrix of hydrogel (FA-Qu-MEs@Gel). FA-Qu-MEs@Gel could be locally injected into the periodontal pocket and sustainedly release drugs. FA-Qu-MEs exhibited excellent ROS scavenging potency by targeting macrophages, resulting M1 phenotype macrophage from to M2 phenotype macrophage. Subsequently, the phenotypic changes of macrophages lead to decreased expression of IL-6 and tumor necrosis factor-α, which inhibited activated Th17, while IL-10 secreted by M2 macrophages promoted Treg differentiation. Finally, the restored Th17/Treg homeostasis reduced the level of IL-17 to accelerate alveolar bone regeneration. This study deigns a novel system that promote alveolar bone regeneration by remodeling Th17/Treg homeostasis via regulating ROS-macrophages polarization cascade for periodontitis treatment.
Assuntos
Emulsões , Homeostase , Hidrogéis , Macrófagos , Periodontite , Espécies Reativas de Oxigênio , Linfócitos T Reguladores , Células Th17 , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Espécies Reativas de Oxigênio/metabolismo , Periodontite/tratamento farmacológico , Periodontite/imunologia , Animais , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Hidrogéis/administração & dosagem , Homeostase/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Masculino , Poloxâmero/química , Células RAW 264.7 , Resinas Acrílicas/química , Regeneração Óssea/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
Immune thrombocytopenia (ITP) is an autoimmune disease caused by T-cell dysfunction. Recently, several studies have shown that a disturbed Th17/Treg balance contributes to the development of ITP. MicroRNAs (miRNAs) are small noncoding RNA moleculesthat posttranscriptionally regulate gene expression. Emerging evidences have demonstrated that miRNAs play an important role in regulating the Th17/Treg balance. In the present study, we found that miR-641 was upregulated in ITP patients. In primary T cells, overexpression of miR-641 could cause downregulation of its target genes STIM1 and SATB1, thus inducing a Th17 (upregulated)/Treg (downregulated) imbalance. Inhibition of miR-641 by a miR-641 sponge in primary T cells of ITP patients or by antagomiR-641 in an ITP murine model could cause upregulation of STIM1 and SATB1, thus restoring Th17/Treg homeostasis. These results suggested that the miR-641-STIM/SATB1 axis plays an important role in regulating the Th17/Treg balance in ITP.
Assuntos
Proteínas de Ligação à Região de Interação com a Matriz , MicroRNAs , Púrpura Trombocitopênica Idiopática , Molécula 1 de Interação Estromal , Linfócitos T Reguladores , Células Th17 , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais de Doenças , Regulação da Expressão Gênica , Proteínas de Ligação à Região de Interação com a Matriz/genética , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/metabolismo , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismoRESUMO
Immunity imbalance of T helper 17 (Th17)/regulatory T (Treg) cells is involved in the pathogenesis of Crohn's disease (CD). Complanatuside A (CA), a flavonol glycoside, exerts anti-inflammatory activities and our study aimed to identify its effect on TNBS-induced colitis and the possible mechanisms. We found that CA alleviated the symptoms of colitis in TNBS mice, as demonstrated by prevented weight loss and colon length shortening, as well as decreased disease activity index scores, inflammatory scores, and levels of proinflammatory factors. Flow cytometry analysis showed that CA markedly reduced the percentage of Th17 cells while increasing the percentage of Treg cells in TNBS mice. Under Th17 cell polarizing conditions, CA inhibited the differentiation of Th17 cells while the Treg cell differentiation was elevated under Treg cell polarizing conditions. Furthermore, it was observed that JAK2 interacted with CA through six hydrogen bonds via molecular docking. The phosphorylation of JAK2/STAT3 was reduced by CA, which might be correlated with the protective effect of CA on colitis. In conclusion, CA reduced the imbalance of Th17/Treg cells by inhibiting the JAK2/STAT3 signaling pathway in TNBS-induced colitis, which may provide novel strategies for CD treatment.