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1.
Immunity ; 56(1): 125-142.e12, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630911

RESUMO

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.


Assuntos
Neoplasias Hepáticas , Células T Matadoras Naturais , Camundongos , Animais , Células Endoteliais/metabolismo , Interleucinas/metabolismo , Interleucina-17/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL
2.
Cell Transplant ; 32: 9636897221149444, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36644879

RESUMO

Clinically, xenotransplantation often leads to T-cell-mediated graft rejection. Immunosuppressive agents including polyclonal regulatory T cells (poly-Tregs) promote global immunosuppression, resulting in serious infections and malignancies in patients. Xenoantigen-expanded Tregs (xeno-Tregs) have become a promising immune therapy strategy to protect xenografts with fewer side effects. In this study, we aimed to identify an efficient and stable subset of xeno-Tregs. We enriched CD27+ xeno-Tregs using cell sorting and evaluated their suppressive functions and stability in vitro via mixed lymphocyte reaction (MLR), real-time polymerase chain reaction, inflammatory induction assay, and Western blotting. A STAT5 inhibitor was used to investigate the relationship between the function and stability of CD27+ xeno-Tregs and the JAK3-STAT5 signaling pathway. A humanized xenotransplanted mouse model was used to evaluate the function of CD27+ xeno-Tregs in vivo. Our results show that CD27+ xeno-Tregs express higher levels of Foxp3, cytotoxic T-lymphocyte antigen-4 (CTLA4), and Helios and lower levels of interleukin-17 (IL-17) than their CD27- counterparts. In addition, CD27+ xeno-Tregs showed enhanced suppressive function in xeno-MLR at ratios of 1:4 and 1:16 of Tregs:responder cells. Under inflammatory conditions, a lower percentage of CD27+ xeno-Tregs secretes IL-17 and interferon-γ (IFN-γ). CD27+ xeno-Tregs demonstrated an upregulated JAK3-STAT5 pathway compared with that of CD27- xeno-Tregs and showed decreased Foxp3, Helios, and CTLA4 expression after addition of STAT5 inhibitor. Mice that received porcine skin grafts showed a normal tissue phenotype and less leukocyte infiltration after reconstitution with CD27+ xeno-Tregs. Taken together, these data indicate that CD27+ xeno-Tregs may suppress immune responses in a xenoantigen-specific manner, which might be related to the activation of the JAK3-STAT5 signaling pathway.


Assuntos
Interleucina-17 , Linfócitos T Reguladores , Transplante Heterólogo , Animais , Humanos , Camundongos , Antígenos Heterófilos/metabolismo , Antígeno CTLA-4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Interleucina-17/metabolismo , Ativação Linfocitária , Fator de Transcrição STAT5/metabolismo , Suínos , Linfócitos T Reguladores/imunologia
3.
J Ethnopharmacol ; 305: 116125, 2023 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-36603786

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a major cause of morbidity and mortality due to repetitive remissions and relapses, and many severe complications, including colitis-associated cancer (CAC). The San-Qi-Xue-Shang-Ning (SQ) formula has been utilized in clinical practice to treat gut diseases, but its pharmacological evidence is limited and awaits elucidation. AIM OF THE STUDY: Here, we elucidated the molecular mechanisms of the SQ formula. MATERIALS AND METHODS: Its therapeutic value in combating UC and CAC was predicted from network pharmacology and weighted gene co-expression network analysis (WGCNA). Experimental colitis models were established by feeding dextran sodium sulfate (DSS) to C57BL/6N mice for 7 days, and they were subjected to the SQ formula for 14 days. High-throughput technologies and biochemical investigations were executed to corroborate the anti-colitis effect. RESULTS: Network pharmacology and WGCNA demonstrated that the targets of the SQ formula were associated with interleukin-17 (IL-17), tumor necrosis factor (TNF), IL-1b and peroxisome proliferators-activated receptor (PPAR) signaling pathways, and correlated with the survival in patients with colorectal cancer. In mice with colitis, the SQ treatment hindered colitis progression in a dose-dependent manner, as evidenced by the rescued colon length and weight loss, improved colonic epithelial integrity, and abolished crypt loss. In addition to the suppressed serum IL-17, TNFα, and IL-1b levels, the SQ-treated colitis mice exhibited decreased colonic protein abundance of hypoxia-inducible factor-1α (HIF-1 α), PPARα, and Caspase3 (Casp3) with an increased PPARγ expression. Concurrently, the high dose of SQ promoted the alternative activation of peritoneal macrophages by increasing Arg1 and inhibiting iNOS2, thereby facilitating the migration of NCM460 cells and controlling TNF-induced reactive oxygen species production and apoptosis in intestinal organoids. In colitis-accompanied dysbiosis, the SQ formula reversed the decreased microbiota diversity indexes and restored the microbiome profile in the murine colitis models. CONCLUSION: The SQ formula is a potent anti-colitis drug that facilitates inflammation resolution and restores gut microbiota homeostasis.


Assuntos
Colite Ulcerativa , Colite , Microbiota , Camundongos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Colite/induzido quimicamente , Colo , Homeostase , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças
4.
Phytomedicine ; 109: 154602, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36610138

RESUMO

BACKGROUND: Depression is a common complication after myocardial infarction (MI) that can seriously affect the prognosis of MI. PURPOSE: To investigate whether formononetin could ameliorate MI injury and depressive behaviours in a mouse model of MI with depression and elucidate its underlying molecular mechanisms. METHODS: Haemodynamic measurements (systolic blood pressure (SYS), the maximum rate of rise of LV pressure (± dp/dtmax)) and behavior tests (tail suspension test, sucrose preference test, forced swimming test) were used to evaluate the effects of formononetin on male C57BL/6N mice after left anterior descending (LAD) coronary artery ligation and chronic unpredictable stress. RT-qPCR, immunohistochemistry, immunofluorescence analysis, western blotting, molecular docking technology, surface plasmon resonance and gene-directed mutagenesis were used to clarify the underlying mechanism. RESULTS: Formononetin significantly suppressed the depressive behaviours and improved cardiac dysfunction in MI with depression mice model. Formononetin inhibited M1 polarization in macrophages/microglia, while promoting M2 polarization. Importantly, elevated serum IL-6 and IL-17A levels were found in patient with MI, and the patient serum induced M1 microglial polarization; however, formononetin reversed the polarization. Further mechanistic studies showed that formononetin inhibited GSK-3ß activity and downstream Notch1 and C/EBPα signaling pathways. Covalent molecular docking showed that formononetin bound to Cys199 of GSK-3ß and it has a high affinity for GSK-3ß. When Cys199 was mutation, the inhibitory effect of formononetin on GSK-3ß activity and M1 polarization in macrophages/microglia were also partly blocked. CONCLUSIONS: Our results firstly uncovered that formononetin improved cardiac function and suppressed depressive behaviours in mice after MI with depression by targeting GSK-3ß to regulate macrophage/microglial polarization. More importantly, IL-6 and IL-17A produced after MI may cause neuroinflammation, which might be the key factors for depression. Formononetin may be a potential drug for treating MI with depression.


Assuntos
Microglia , Infarto do Miocárdio , Camundongos , Masculino , Animais , Microglia/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Interleucina-17/metabolismo , Depressão/tratamento farmacológico , Depressão/etiologia , Interleucina-6/metabolismo , Simulação de Acoplamento Molecular , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Macrófagos/metabolismo
5.
PLoS One ; 18(1): e0280601, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662733

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Green-lipped mussel (GLM) has chondro-modulatory and anti-inflammatory properties, but the mechanism underlying the effect of GLM on RA is unclear. To investigate the roles of GLM on the pathogenesis of RA, we examined the effects of GLM in collagen-induced arthritis (CIA) mice and osteoclast differentiation. GLM was orally administrated CIA mice at 3 weeks after chicken type II collagen (CII) immunizations. GLM reduced arthritis severity and the histologic score of CIA mice compared to vehicle. The expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-17) was decreased in the ankle joints of GLM-treated CIA mice. The expression of CD4+ IL-17+ cells decreased in ex vivo splenocytes and the spleens of GLM-treated CIA mice. Moreover, GLM inhibited TRAP+ multinucleated cells among mouse bone marrow-derived monocytes/macrophages (BMM), and the expression of osteoclast-related genes in mouse BMMs and human monocytes in vitro. These results suggest that GLM has potential as a therapeutic agent that can improve disease by controlling pathologic immune cells and osteoclastogenesis.


Assuntos
Artrite Experimental , Artrite Reumatoide , Bivalves , Camundongos , Humanos , Animais , Osteogênese , Interleucina-17/metabolismo , Artrite Reumatoide/tratamento farmacológico , Osteoclastos/metabolismo , Citocinas/metabolismo , Artrite Experimental/tratamento farmacológico , Bivalves/metabolismo
6.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675261

RESUMO

Retinal neovascularization occurs in proliferative diabetic retinopathy, neovascular glaucoma, and age-related macular degeneration. This type of retinal pathology normally occurs in the later stages of these ocular diseases and is a prevalent cause of vision loss. Previously, we determined that Interleukin (IL)-17A plays a pivotal role in the onset and progression of non-proliferative diabetic retinopathy in diabetic mice. Unfortunately, none of our diabetic murine models progress to proliferative diabetic retinopathy. Hence, the role of IL-17A in vascular angiogenesis, neovascularization, and the onset of proliferative diabetic retinopathy was unclear. In the current study, we determined that diabetes-mediated IL-17A enhances vascular endothelial growth factor (VEGF) production in the retina, Muller glia, and retinal endothelial cells. Further, we determined that IL-17A can initiate retinal endothelial cell proliferation and can enhance VEGF-dependent vascular angiogenesis. Finally, by utilizing the oxygen induced retinopathy model, we determined that IL-17A enhances retinal neovascularization. Collectively, the results of this study provide evidence that IL-17A plays a pivotal role in vascular proliferation in the retina. Hence, IL-17A could be a potentially novel therapeutic target for retinal neovascularization, which can cause blindness in multiple ocular diseases.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Neovascularização Retiniana , Camundongos , Animais , Neovascularização Retiniana/metabolismo , Retinopatia Diabética/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Retina/metabolismo
7.
Gen Physiol Biophys ; 42(1): 13-24, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36705301

RESUMO

Guillain-Barré syndrome (GBS) is an acute immune-mediated paralytic neuropathy with variable disease course and outcome. In this study, we aimed to investigate the therapeutic effects of celastrol on GBS and uncover its underlying mechanisms. Experimental autoimmune neuritis (EAN) is a typical animal model for GBS, and thus an EAN rat model was established with the injection of celastrol or/and LPS. We assessed the body weights and EAN clinical scores of rats. HE staining, flow cytometry, RT-qPCR, and Western blotting were respectively employed to measure pathological damage, proportions of cells (Th1, Th17, and Treg), Th1/Th17 cell differentiation-related mRNAs (IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23) and TLR4/NF-κB/STAT3 pathway-related proteins (TLR4, NF-κB, p-NF-κB, STAT3, and p-STAT3). We found that celastrol attenuated clinical symptoms and pathological damage of GBS in EAN rats. Moreover, celastrol down-regulated Th1 and Th17 cell proportions, and the levels of IFN-γ, TBX21, IL-18, RORγT, IL-17, and IL-23 in EAN rats. Meanwhile, the levels of TLR4, p-NF-κB, and p-STAT3 were decreased by celastrol. Taken together, celastrol could restrain Th1/Th17 cell differentiation through inhibition of the TLR4/NF-κB/STAT3 pathway in EAN rats. Our findings suggest that celastrol may exert therapeutic effects on GBS by suppressing TLR4/NF-κB/STAT3 pathway-mediated Th1/Th17 cell differentiation.


Assuntos
Síndrome de Guillain-Barré , Ratos , Animais , Síndrome de Guillain-Barré/tratamento farmacológico , Síndrome de Guillain-Barré/patologia , Interleucina-17/metabolismo , Interleucina-17/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/uso terapêutico , NF-kappa B/metabolismo , Interleucina-18/metabolismo , Interleucina-18/farmacologia , Interleucina-18/uso terapêutico , Células Th17/metabolismo , Receptor 4 Toll-Like , Diferenciação Celular , Interleucina-23/metabolismo , Interleucina-23/farmacologia , Interleucina-23/uso terapêutico
8.
Immun Inflamm Dis ; 11(1): e768, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36705412

RESUMO

OBJECTIVE: Helicobacter pylori is planted in the human stomach and is the most common cause of chronic gastritis, which produced specific local and systemic humoral immunity, while the associations of these immune responses and H. pylori in the development of chronic gastritis remain unclear. METHODS: This study analyzed histology, the number of Th22 and regulatory T (Treg) cells, and the levels of inflammation- and gastritis-related indicators between 22 H. pylori-infected and 24 non-H. pylori-infected chronic gastritis patients by hematoxylin-eosin staining, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR, and flow cytometry analysis. RESULTS: This study found that the pathological damage degree of gastric mucosa in H. pylori infection patients was more serious. In the H. pylori-infected patient serum, the gastrin, G-17, interleukins (IL)-22, transforming growth factor (TGF)-ß, tumor necrosis factor (TNF)-α, IL-4, and IL-17A levels were notably raised, while the interferon (IFN)-γ level was inhibited, and in gastric mucosa, and except IFN-γ, the IL-22, forkhead box P3 (Foxp3), TNF-α, IL-4, and IL-17A mRNA levels were raised too. The receiver operating characteristic curve analysis indicates serum IL-22, TGF-ß, TNF-α, IL-4, and IL-17A are suitable for differential diagnosis of H. pylori infection. In addition, in the peripheral blood, the percentages of the IL-22+ CD4+ and Foxp3+ CD4+ T cells were raised with H. pylori infection. The positive correlation between IL-22 and Foxp3 mRNA levels and the degree of H. pylori colonization and gastric mucositis by Pearson's correlation analysis. CONCLUSIONS: Treg and Th22 cells were positively associated with the degree of H. pylori infection and the severity of gastritis. In summary, this study provides an experimental basis for the study of the eradication of H. pylori and the biological mechanism of chronic gastritis.


Assuntos
Gastrite , Infecções por Helicobacter , Helicobacter pylori , Humanos , Linfócitos T Reguladores , Interleucina-17/metabolismo , Helicobacter pylori/genética , Fator de Necrose Tumoral alfa/metabolismo , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Interleucina-4 , Gastrite/metabolismo , Gastrite/patologia , Fator de Crescimento Transformador beta/metabolismo , Interferon gama/metabolismo , RNA Mensageiro/metabolismo , Fatores de Transcrição Forkhead/genética
9.
Infect Immun ; 91(1): e0037822, 2023 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-36602381

RESUMO

Recent studies have found that the coexistence of fungi and bacteria in the airway may increase the risk of infection, contribute to the development of pneumonia, and increase the severity of disease. Interleukin 17A (IL-17A) plays important roles in host resistance to bacterial and fungal infections. The objective of this study was to determine the effects of IL-17A on Acinetobacter baumannii-infected rats with a previous Candida albicans airway inoculation. The incidence of A. baumannii pneumonia was higher in rats with C. albicans in the airway than in noninoculated rats, and it decreased when amphotericin B was used to clear C. albicans, which influenced IL-17A levels. IL-17A had a protective effect in A. baumannii pneumonia associated with C. albicans in the airway. Compared with A. baumannii-infected rats with C. albicans in the airway that did not receive IL-17A, recombinant IL-17A (rIL-17A) supplementation decreased the incidence of A. baumannii pneumonia (10/15 versus 5/17; P = 0.013) and the proportion of neutrophils in the lung (84 ± 3.5 versus 74 ± 4.3%; P = 0.033), reduced tissue destruction and inflammation, and decreased levels of myeloperoxidase (MPO) (1.267 ± 0.15 versus 0.233 ± 0.06 U/g; P = 0.0004), reactive oxygen species (ROS) (132,333 ± 7,505 versus 64,667 ± 10,115 AU; P = 0.0007) and lactate dehydrogenase (LDH) (2.736 ± 0.05 versus 2.1816 ± 0.29 U/g; P = 0.0313). In vitro experiments revealed that IL-17A had no significant effect on the direct migration ability and bactericidal capability of neutrophils. However, IL-17A restrained lysis cell death and increased apoptosis of neutrophils (2.9 ± 1.14 versus 7 ± 0.5%; P = 0.0048). Taken together, our results suggest that C. albicans can depress IL-17A levels, which when supplemented may have a regulatory function that limits the accumulation of neutrophils in inflammatory areas, providing inflammatory response homeostasis.


Assuntos
Infecções por Acinetobacter , Acinetobacter baumannii , Pneumonia Bacteriana , Pneumonia , Ratos , Animais , Candida albicans/metabolismo , Interleucina-17/metabolismo , Acinetobacter baumannii/metabolismo , Pulmão/metabolismo , Neutrófilos/metabolismo , Bactérias/metabolismo
10.
Mediators Inflamm ; 2023: 1195149, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36643586

RESUMO

Purpose: To investigate whether the Notch signaling pathway participates in the occurrence and development of experimental autoimmune thyroiditis (EAT) by affecting the differentiation and function of Th17 cells. Materials and Methods: Experimental mice were randomly divided into a control group, an EAT-A group (porcine thyroid immunoglobulin- (pTg-) treated mice) and an EAT-B group (treated with the DAPT γ-secretase inhibitor before pTg). HE staining, IHC staining, flow cytometry, RT-qPCR, and ELISA were used to evaluate the degrees of thyroiditis, detect the percentage of Th17 cells and measure the expression of retinoic acid-related orphan receptor gamma t (RORγt), interleukin-17A (IL-17A), and the main components of the Notch signaling pathway. Results: The degrees of thyroiditis, the proportions of Th17 cells, and the expression of RORγt and IL-17A were significantly decreased in the EAT-B group after blocking the Notch signaling pathway by DAPT, and these parameters were significantly increased in the EAT-A group compared to the control group (all P < 0.05). Additionally, the Th17 cell percentages and IL-17A concentrations in spleen mononuclear cells (SMCs) from EAT-A mice decreased in a dose-dependent manner after DAPT treatment in vitro (all P < 0.01). Correlation analyses revealed that the Th17 cell percentages were positively correlated with the serum TgAb titers, Notch pathway-related mRNA expression levels, and IL-17A concentrations in EAT mice (all P < 0.05). Conclusions: The expression of Notch signaling pathway components was upregulated in EAT mice, but blockade of the Notch signaling pathway alleviated the degree of thyroiditis, decreased the Th17 cell proportions, and downregulated the IL-17A effector cytokine both in vivo and in vitro. These findings suggested that the Notch signaling pathway may be involved in the pathogenesis of thyroid autoimmune injury in EAT mice by promoting the differentiation of Th17 cells.


Assuntos
Doença de Hashimoto , Tireoidite Autoimune , Camundongos , Animais , Tireoidite Autoimune/patologia , Interleucina-17/metabolismo , Células Th17/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , Diferenciação Celular , Transdução de Sinais
11.
J Exp Med ; 220(3)2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36515659

RESUMO

The small intestinal lamina propria contains large numbers of IFNγ-producing T helper (Th1) cells that play important roles in intestinal homeostasis and host defense, but the mechanisms underlying their development remain poorly understood. Here, we demonstrate that Th1 cells accumulate in the SI-LP after weaning and are maintained there long term. While both Th17 and Th1 cell accumulation in the SI-LP was microbiota dependent, Th1 cell accumulation uniquely required IL-27 and MHCII expression by cDC1. This reflected a requirement for IL-27 signaling in the priming of Th1 cells rather than for their maintenance once in the mucosa. cDC1-derived IL-27 was essential for maintaining the Th1-Th17 balance within the SI-LP, and in its absence, remaining Th1 cells expressed enhanced levels of Th17 signature genes. In conclusion, we identify cDC1-derived IL-27 as a key regulator of SI-LP Th1-Th17 cell homeostasis.


Assuntos
Linfócitos T CD4-Positivos , Interleucina-27 , Camundongos , Animais , Linfócitos T CD4-Positivos/metabolismo , Interleucina-27/metabolismo , Interleucina-17/metabolismo , Células Th17/metabolismo , Células Th1/metabolismo , Mucosa Intestinal/metabolismo , Homeostase
12.
Exp Neurol ; 359: 114263, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36336029

RESUMO

BACKGROUND: Septic-associated encephalopathy (SAE) is a critical manifestation of sepsis that leads to long-term cognitive impairment. Interleukin (IL)-17A has been shown to mediate neuronal apoptosis in central nervous system diseases, while oxidative stress has been found to have a detrimental effect in SAE. However, the relationship between IL-17A and oxidative stress in SAE remains unclear. This study aimed to investigate the effects of secukinumab on alleviating cognitive impairment in a rat model of sepsis, as well as examine its underlying molecular mechanism of action. METHODS: A total of 282 male 8-week-old Sprague-Dawley rats were randomly subjected to cecal ligation and puncture (CLP) or sham treatment followed by volume resuscitation immediately after surgery. Secukinumab was administered intranasally 1 h post-CLP. Rats were given the p-ERK activator ceramide C6 intracerebroventricularly (i.c.v) 24 h before CLP surgery. Recombinant rIL-17A was administered i.c.v. at 0 h in naive rats, followed by intraperitoneal injection of the AKT inhibitor GDC0068 1 h post-rIL-17A injection. Clinical scores, body weight, and survival rate were assessed. In addition, immunofluorescence staining, neurobehavioral tests, Nissl staining, and western blotting were performed. Cognitive function was assessed 15-20 days post-CLP using the Morris water maze test. RESULTS: IL-17A and IL-17RA protein expression levels in the rat hippocampus increased and peaked 24 h post-CLP. Furthermore, IL-17RA was found to be expressed in neurons. The survival rate after CLP was 50%. Following CLP, an increased clinical score and significant decrease in body weight were observed. However, treatment with secukinumab led to a decrease in the clinical score of rats 24 h post-CLP. CLP resulted in spatial and memory impairment and anxiety-like behaviors in rats, while secukinumab treatment significantly alleviated cognitive impairment compared to the CLP group (p < 0.05). In addition, oxidative stress and neuronal apoptosis were found to be increased in the CLP group, while secukinumab significantly reduced oxidative stress and neuronal apoptosis in the hippocampus following CLP. Furthermore, secukinumab treatment led to a significant decrease in the protein expression levels of p-AKT, p-ERK1/2, Romo1, and Bax, together with increased Bcl-2 protein expression. Finally, treatment with ceramide C6 and GDC0068 abolished the neuroprotective effects of secukinumab post-CLP. CONCLUSION: Our results demonstrated that secukinumab attenuated oxidative stress and neuronal apoptosis and partially ameliorated cognitive impairment via the IL-17RA/AKT/ERK1/2 pathway in a rat model of sepsis. Thus, secukinumab may be a potential therapeutic strategy for septic patients.


Assuntos
Disfunção Cognitiva , Encefalopatia Associada a Sepse , Sepse , Animais , Ratos , Masculino , Interleucina-17/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Sistema de Sinalização das MAP Quinases , Sepse/complicações , Sepse/tratamento farmacológico , Apoptose , Estresse Oxidativo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Ceramidas/farmacologia , Peso Corporal
13.
J Cutan Med Surg ; 27(1_suppl): 3S-24S, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36519621

RESUMO

Cytokines in the interleukin (IL)-23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.


Assuntos
Inibidores de Janus Quinases , Psoríase , Adulto , Humanos , Janus Quinases/metabolismo , Janus Quinases/uso terapêutico , Interleucina-17/metabolismo , Transdução de Sinais , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/uso terapêutico , TYK2 Quinase/metabolismo , TYK2 Quinase/uso terapêutico , Psoríase/patologia , Interleucina-23 , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico
14.
FASEB J ; 37(1): e22690, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36468880

RESUMO

Fatty amide hydrolase (FAAH) is a key degradation enzyme of the endocannabinoid system, mainly responsible for the hydrolysis of arachidonic acid ethanolamine (AEA). Previous investigations have shown that FAAH is involved in a series of biological processes, such as inflammation, immune regulation, and transmembrane signal transduction of neurons. Endogenous cannabinoids and cannabinoid receptors have been reported to participate in the regulation of bone homeostasis by regulating the differentiation of osteoblasts and osteoclasts. We hypothesized that FAAH may play an important role in osteoclastogenesis based on the above evidence. The present study found that the FAAH expression was increased at both mRNA and protein levels during RANKL-induced osteoclastogenesis. Pharmacological and genetic inhibition of FAAH in bone marrow-derived macrophages (BMMs) inhibited osteoclastogenesis, F-actin ring formation, bone resorption, and osteoclast-specific gene expression in vitro. Moreover, intragastric administration of the FAAH inhibitor PF-04457845(PF) ameliorated ovariectomy (OVX)-induced bone loss in mice. Further investigation revealed that nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways were inhibited by PF treatment and FAAH knockdown. RNAseq indicated that the IL17 pathway was blocked by PF, and administration of recombinant murine IL17 protein could partially restore osteoclastogenesis and activate NF-κB and MAPK pathways. To sum up, our findings demonstrate that targeting FAAH could be a promising candidate strategy for treating osteoclast-related diseases, especially osteoporosis.


Assuntos
Amidoidrolases , Reabsorção Óssea , Interleucina-17 , Osteogênese , Animais , Feminino , Camundongos , Reabsorção Óssea/etiologia , Reabsorção Óssea/prevenção & controle , Diferenciação Celular , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Ovariectomia/efeitos adversos , Ligante RANK/metabolismo , Amidoidrolases/antagonistas & inibidores , Interleucina-17/metabolismo
15.
Cell Immunol ; 383: 104655, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36516652

RESUMO

Using a murine collagen-induced arthritis model, we characterized the heterogeneity of synovial CD8+ T cells based on the expression of chemokine receptors, cytokines, and nuclear transcription factors. Four subsets, i.e. CXCR3-CCR4- cells, CXCR3+CCR4- cells, CXCR3+CCR4+ cells, and CXCR3-CCR4+ cells, were present in synovial CD8+CD62L-CCR6+IL-23R+CCR10- T cells. CXCR3-CCR4- cells belonged to exhausted CD8+ T cells. CXCR3+CCR4- cells were Tc17.1 cells expressing both IL-17A and IFN-γ. CXCR3+CCR4+ cells were transitional Tc17.1 cells expressing IL-17A but lower IFN-γ, and CXCR3-CCR4+ cells were Tc17 cells expressing IL-17A but no IFN-γ. Transitional Tc17.1 cells can differentiate into Tc17.1 cells in vitro under the instruction of IL-12. Tc17.1 cells and transitional Tc17.1 cells strongly induced the expression of pro-inflammatory mediators in synovial fibroblasts, whereas Tc17 cells were less potent in doing so. IFN-γ was involved in the higher pathogenicity of Tc17.1 cells and transitional Tc17.1 cells on synovial fibroblasts. This study expands the understanding of Tc17 biology by unveiling the phenotypic and functional heterogeneity of synovial IL-17A-expressing CD8+ T cells. These heterogeneous IL-17A-expressing CD8+ T cells could be novel therapeutic targets in future arthritis treatment.


Assuntos
Artrite Experimental , Linfócitos T CD8-Positivos , Interleucina-17 , Membrana Sinovial , Células Th17 , Animais , Camundongos , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos T CD8-Positivos/imunologia , Interleucina-17/metabolismo , Membrana Sinovial/imunologia , Células Th17/imunologia
16.
Int J Mol Sci ; 23(24)2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36555642

RESUMO

Psoriasis is a chronic, immune-mediated inflammatory skin disorder. Rheum palmatum L. is a common traditional medicinal herb with anti-inflammatory and immunomodulatory activities. This study aimed to investigate the anti-psoriatic effects of the ethanolic extract from R. palmatum L. (RPE) and its chemical constituents, as well as the mechanisms underlying their therapeutic significance. An imiquimod (IMQ)-induced psoriasis-like mouse model was used to examine the anti-psoriatic effect of RPE in vivo. Network pharmacological analysis was performed to investigate the potential targets and related pathways of the RPE components, including rhein, emodin, chrysophanol, aloe-emodin, and physcion. The anti-inflammatory effects and underlying mechanisms of these components were examined using in vitro models. Topical application of RPE alleviated psoriasis-like symptoms and reduced levels of inflammatory cytokines and proliferation markers in the skin. Network pharmacological analysis revealed that RPE components target 20 genes that are linked to psoriasis-related pathways, such as IL-17, MAPK, and TNF signaling pathways. Among the five components of RPE, rhein and emodin showed inhibitory effects on TNF-α and IL-17 production in EL-4 cells, attenuated the production of CXCL8, CXCL10, CCL20, and MMP9, and reduced proliferation in HaCaT cells. Chrysophanol, aloe-emodin, and physcion were less effective than rhein and emodin in suppressing inflammatory responses and keratinocyte proliferation. The effects of these compounds might occur through the inhibition of the ERK, STAT3, and NF-κB signaling pathways. This study suggested the anti-psoriatic effect of RPE, with rhein and emodin as the main contributors that regulate multiple signaling pathways.


Assuntos
Emodina , Psoríase , Rheum , Animais , Camundongos , Antraquinonas/farmacologia , Anti-Inflamatórios/farmacologia , Emodina/farmacologia , Interleucina-17/metabolismo , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Rheum/química
17.
Int J Mol Sci ; 23(23)2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36498953

RESUMO

Psoriasis is a chronic autoimmune disease, and until now, it remains an incurable disease. Therefore, the development of new drugs or agents that ameliorate the disease will have marketing potential. Taiwanofungus camphoratus (TC) is a specific fungus in Taiwan. It is demonstrated to have anticancer, anti-inflammation, and hepatoprotective effects. However, the effects of TC fermented extract on psoriasis are under investigation. In this research, we studied the ability of TC on antioxidative activity and the efficacy of TC on interleukin-17 (IL-17A)-induced intracellular oxidative stress, inflammation-relative, and proliferation-relative protein expression in human keratinocytes. The results of a DPPH radical scavenging assay, reducing power assay, and hydroxyl peroxide inhibition assay indicated that TC has a potent antioxidant ability. Furthermore, TC could reduce IL-17A-induced intracellular ROS generation and restore the NADPH level. In the investigation of pathogenesis, we discovered TC could regulate inflammatory and cell proliferation pathways via p-IKKα/p-p65 and p-mTOR/p-p70S6k signaling pathways in human keratinocytes. In conclusion, TC showed characteristics such as antioxidant, anti-inflammatory, and anti-psoriatic-associated responses. It is expected to be developed as a candidate for oxidative-stress-induced skin disorders or psoriasis treatment.


Assuntos
Produtos Biológicos , Queratinócitos , Psoríase , Humanos , Anti-Inflamatórios/farmacologia , Células HaCaT/efeitos dos fármacos , Células HaCaT/metabolismo , Interleucina-17/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , NF-kappa B/metabolismo , Psoríase/patologia , Serina-Treonina Quinases TOR/metabolismo , Produtos Biológicos/farmacologia
18.
Ann Clin Lab Sci ; 52(6): 884-894, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36564065

RESUMO

OBJECTIVE: To investigate the regulatory effect and mechanism of methyltransferase-like protein 3 (METTL3)-mediated N6-methyladenosine methylation (m6A) on forkhead box protein 3 (Foxp3) levels and the proportion of regulatory T (Treg) cells in the peripheral blood of patients with asthma. METHODS: Flow cytometry and ELISA were used to detect the differences in the proportions of Treg cells and serum interleukins (ILs) 4 and 7, respectively, in the peripheral blood between healthy individuals and patients with different asthma conditions. Reverse transcription-quantitative PCR (RT-qPCR) and Western blotting were used to detect the mRNA and protein expression levels, respectively, of METTL3 and Foxp3 in CD4+ T cells in the peripheral blood samples of different groups. M6A blot and m6A coimmunoprecipitation-PCR were used to detect the global and Foxp3 mRNA m6A levels, respectively, in the peripheral blood CD4+ T cells. CD4+ T cells collected from the peripheral blood of patients with asthma were subjected to in vitro transfection to knockdown the METTL3 levels and observe changes in the Foxp3 mRNA, protein, m6A levels, and RNA stability. Flow cytometry and ELISA were used to detect the changes in the Treg cell proportion and IL-4 and IL-17 levels in the cell culture supernatant. RESULTS: Compared with the healthy individuals, the ratio of Treg cells to peripheral blood CD4+ T cells was significantly decreased and the Foxp3 mRNA and protein expression was downregulated in patients with asthma with disease progression. The Foxp3 mRNA and protein expression levels were positively correlated with the Treg cell proportion and negatively correlated with IL-17 expression. The global and Foxp3 mRNA m6A levels were increased in the peripheral blood CD4+ T cells of patients with asthma. METTL3 expression was significantly higher in the peripheral blood CD4+ T cells of patients with asthma compared with healthy individuals. After METTL3 knockdown, the Foxp3 mRNA m6A level was reduced, and the stability of Foxp3 mRNA and protein expression was increased. YTHDF2 could bind to the m6A site in 3'UTR of Foxp3 mRNA. Knockdown of YTHDF2 regulated the level and stability of Foxp3 mRNA. METTL3 knockdown reduced the ratio of Treg cells to CD4+ T cells and the IL-4 and IL-17 secretion levels from CD4+ T cells in the peripheral blood of patients with asthma. CONCLUSIONS: High METTL3 expression in the peripheral blood CD4+ T cells of patients with asthma increased the m6A level and reduced the stability of Foxp3 mRNA in a YTHDF2-dependent way, thereby reducing the expression of Foxp3 and the proportion of Treg cells.


Assuntos
Asma , Linfócitos T Reguladores , Humanos , Metilação , Linfócitos T Reguladores/metabolismo , Interleucina-4/metabolismo , Interleucina-17/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , Asma/genética
19.
Arthritis Res Ther ; 24(1): 280, 2022 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-36564791

RESUMO

BACKGROUND: Interstitial lung disease, a common extra-articular complication of connective tissue disease, is characterized by progressive and irreversible pulmonary inflammation and fibrosis, which causes significant mortality. IL-22 shows a potential in regulating chronic inflammation and possibly plays an anti-fibrotic role by protecting epithelial cells. However, the detailed effects and underlying mechanisms are still unclear. In this study, we explored the impact of IL-22 on pulmonary fibrosis both in vivo and in vitro. METHODS: To induce pulmonary fibrosis, wild-type mice and IL-22 knockout mice were intratracheally injected with bleomycin followed by treatments with recombinant IL-22 or IL-17A neutralizing antibody. We investigated the role of IL-22 on bleomycin-induced pulmonary fibrosis and the mechanism in the possible interaction between IL-22 and IL-17A. Fibrosis-related genes were detected using RT-qPCR, western blot, and immunofluorescence. Inflammatory and fibrotic changes were assessed based on histological features. We also used A549 human alveolar epithelial cells, NIH/3T3 mouse fibroblast cells, and primary mouse lung fibroblasts to study the impact of IL-22 on fibrosis in vitro. RESULTS: IL-22 knockout mice showed aggravated pulmonary fibrosis compared with wild-type mice, and injection of recombinant IL-22 decreased the severe fibrotic manifestations in IL-22 knockout mice. In cell culture assays, IL-22 decreased protein levels of Collagen I in A549 cells, NIH/3T3 cells, and primary mouse lung fibroblasts. IL-22 also reduced the protein level of Collagen I in NIH/3T3 cells which were co-cultured with T cells. Mechanistically, IL-22 reduced the Th17 cell proportion and IL-17A mRNA level in lung tissues, and treatment with an IL-17A neutralizing antibody alleviated the severe pulmonary fibrosis in IL-22 knockout mice. The IL-17A neutralizing antibody also reduced Collagen I expression in NIH/3T3 cells in vitro. Knockdown of IL-17A with siRNAs or administration of IL-22 in NIH/3T3 cells and MLFs decreased expression of Collagen I, an effect blocked by concurrent use of recombinant IL-17A. CONCLUSIONS: IL-22 mediated an anti-fibrogenesis effect in the bleomycin-induced pulmonary fibrosis model and this effect was associated with inhibition of IL-17A.


Assuntos
Fibrose Pulmonar , Camundongos , Humanos , Animais , Fibrose Pulmonar/metabolismo , Bleomicina/toxicidade , Interleucina-17/metabolismo , Pulmão/patologia , Fibrose , Colágeno Tipo I/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BL
20.
Biomolecules ; 12(12)2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36551310

RESUMO

Molecular farming utilizes plants as a platform for producing recombinant biopharmaceuticals. Duckweed, the smallest and fastest growing aquatic plant, is a promising candidate for molecular farming. However, the efficiency of current transformation methods is generally not high in duckweed. Here, we developed a fast and efficient transformation procedure in Lemna minor ZH0403, requiring 7-8 weeks from screening calluses to transgenic plants with a stable transformation efficiency of 88% at the DNA level and 86% at the protein level. We then used this transformation system to produce chicken interleukin-17B (chIL-17B). The plant-produced chIL-17B activated the NF-κB pathway, JAK-STAT pathway, and their downstream cytokines in DF-1 cells. Furthermore, we administrated chIL-17B transgenic duckweed orally as an immunoadjuvant with mucosal vaccine against infectious bronchitis virus (IBV) in chickens. Both IBV-specific antibody titer and the concentration of secretory immunoglobulin A (sIgA) were significantly higher in the group fed with chIL-17B transgenic plant. This indicates that the duckweed-produced chIL-17B enhanced the humoral and mucosal immune responses. Moreover, chickens fed with chIL-17B transgenic plant demonstrated the lowest viral loads in different tissues among all groups. Our work suggests that cytokines are a promising adjuvant for mucosal vaccination through the oral route. Our work also demonstrates the potential of duckweed in molecular farming.


Assuntos
Adjuvantes de Vacinas , Araceae , Animais , Interleucina-17/genética , Interleucina-17/metabolismo , Janus Quinases/genética , Transdução de Sinais , Galinhas , Fatores de Transcrição STAT/genética , Citocinas/metabolismo , Adjuvantes Imunológicos/farmacologia , Araceae/genética , Araceae/metabolismo , Transformação Genética
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