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Malassezia, the most abundant fungal commensal on the mammalian skin, has been linked to several inflammatory skin diseases such as atopic dermatitis, seborrheic dermatitis and psoriasis. This study reveals that epicutaneous application with Malassezia globosa (M. globosa) triggers skin inflammation in mice. RNA-sequencing of the resulting mouse lesions indicates activation of Interleukin-17 (IL-17) signaling and T helper 17 (Th17) cells differentiation pathways by M. globosa. Furthermore, our findings demonstrate a significant upregulation of IL-23, IL-23R, IL-17A, and IL-22 expressions, along with an increase in the proportion of Th17 and pathogenic Th17 cells in mouse skin exposed to M. globosa. In vitro experiments illustrate that M. globosa prompts human primary keratinocytes to secrete IL-23 via TLR2/MyD88/NF-κB signaling. This IL-23 secretion by keratinocytes is shown to be adequate for inducing the differentiation of pathogenic Th17 cells in the skin. Overall, these results underscore the significant role of Malassezia in exacerbating skin inflammation by stimulating IL-23 secretion by keratinocytes and promoting the differentiation of pathogenic Th17 cells.
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Diferenciación Celular , Interleucina-23 , Queratinocitos , Malassezia , Células Th17 , Malassezia/inmunología , Queratinocitos/microbiología , Queratinocitos/inmunología , Queratinocitos/metabolismo , Células Th17/inmunología , Animales , Interleucina-23/metabolismo , Humanos , Ratones , Transducción de Señal , FN-kappa B/metabolismo , Receptor Toll-Like 2/metabolismo , Interleucina-17/metabolismo , Piel/microbiología , Piel/patología , Piel/inmunología , Modelos Animales de Enfermedad , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Células Cultivadas , Ratones Endogámicos C57BL , Interleucina-22RESUMEN
Introduction: Equine asthma (EA) is a common disease of adult horses with chronic respiratory pathology and common neutrophilic airway inflammation. It presents with hyperreactivity to hay dust components such as molds, and underlying dysregulated T cell responses have been suggested. Thus far, T cells have been analysed in EA with conflicting results and the antigen reactivity of T cells has not been demonstrated. Serological and epidemiological data point to the relevance of Aspergillus fumigatus as an antigen source in EA. Here, we aimed to identify and characterise Aspergillus antigen-reactive T cells in EA. Methods: Cryopreserved bronchoalveolar lavage cells (BALC) and peripheral blood mononuclear cells (PBMC) from healthy horses (HE, n=9) and those with mild-moderate (MEA, n=3) or severe asthma (SEA, n=8) were stimulated in vitro with the recombinant A. fumigatus antigens Asp f 1, or Asp f 7 combined with Asp f 8, to assess antigen reactivity, and with phorbol-12-myristat-13-acetate and ionomycin (P/i) to assess overall T cell reactivity. Stimulated cells were analysed by flow cytometry for CD4, CD8, IL-17, IL-4, and IFN-γ. Cytokine expression in all lymphocytes, and in CD4+ or CD8+ T cells, was quantified and compared between the groups. In BAL fluid (BALF), soluble cytokines and chemokines were quantified by bead-based assays. Results: Antigen restimulation of BALC with Asp f 1 or Asp f 7/8 provoked higher frequencies of IL-17+ lymphocytes, CD4+IL-17+ Th17 cells, and CD4+IL-4+ Th2 cells in SEA than in HE, whereas MEA and HE were similar. Antigen stimulation of PBMC did not result in group differences. P/i stimulation of BALC resulted in increased IL-17+ lymphocyte and CD4+IL-17+ Th17 cell frequencies in MEA compared with HE but the limited number of horses with MEA must be considered. P/i-stimulated PBMC from MEA or SEA contained more IL-17+ lymphocytes compared with HE. Cytokines were hardly detected in BALF and similar between the groups but CCL2 and CCL5 concentrations were increased in BALF from SEA or MEA, respectively, compared with HE. Conclusion: Horses with SEA have increased Aspergillus antigen-reactive Th17 cells in their airways, emphasising local T cell responses to this mold, which were quantified in EA for the first time here.
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Antígenos Fúngicos , Aspergillus fumigatus , Asma , Líquido del Lavado Bronquioalveolar , Citocinas , Enfermedades de los Caballos , Células Th17 , Animales , Células Th17/inmunología , Asma/inmunología , Aspergillus fumigatus/inmunología , Caballos/inmunología , Antígenos Fúngicos/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Enfermedades de los Caballos/inmunología , Enfermedades de los Caballos/microbiología , Citocinas/metabolismo , Masculino , FemeninoRESUMEN
Proton pump inhibitors (PPIs), such as omeprazole, are the most commonly prescribed drugs. Treatment with PPIs alters gut microbiota composition and reduces the production of reactive oxygen (ROS) and proinflammatory IL-1ß, IL-6, and TNF-α cytokines. Here, using the T cell-dependent contact hypersensitivity (CHS) response, an animal model of allergic contact dermatitis (ACD) that affects up to 30% of the population, we demonstrated that a two-week omeprazole treatment suppresses the development of CHS. Omeprazole treatment before CHS induction, reduced inflammatory response in ears measured by ear swelling, ear biopsy weight, MPO activity, and proinflammatory cytokine production. These changes were associated with reduced frequency of TCRαß+ CD4+ IL-17A+ and TCRαß+ CD8+ IL-17A+ T cells and increased frequency of TCRαß+ CD4+ CD25+ FoxP3+ Treg, and TCRαß+ CD4+ IL-10+ Tr1 cells in peripheral lymphoid organs. Omeprazole treatment decreased the production of ROS, TNF-α, and IL-6, which supported Th17 cell induction, and increased the frequency of Clostridium cluster XIVab and Lactobacillus, implicated in Treg cell induction. The fecal microbiota transplantation (FMT) experiment confirmed the role of omeprazole-induced changes in gut microbiota profile in CHS suppression. Our data suggests that omeprazole ameliorates inflammatory response mediated by T-cells.
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Disbiosis , Microbioma Gastrointestinal , Omeprazol , Inhibidores de la Bomba de Protones , Linfocitos T Reguladores , Células Th17 , Animales , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Células Th17/inmunología , Células Th17/metabolismo , Ratones , Linfocitos T Reguladores/inmunología , Omeprazol/farmacología , Modelos Animales de Enfermedad , Citocinas/metabolismo , Femenino , Ratones Endogámicos C57BL , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/etiologíaRESUMEN
Keloids are characterized histologically by excessive fibroblast proliferation and connective tissue deposition, and clinically by scar tissue extending beyond the original site of skin injury. These scars can cause pruritus, pain, physical disfigurement, anxiety, and depression. As a result, keloid patients often have a diminished quality of life with a disproportionate burden on ethnic minorities. Despite advances in understanding keloid pathology, there is no effective Food and Drug Administration (FDA)-approved pharmacotherapy. Recent studies have highlighted the possible pathologic role of T helper (Th)17 cells and interleukin (IL)-17 in keloid formation, as well as their implication in other inflammatory disorders. This systematic review characterizes the role of Th17 cells and IL-17 in keloid pathogenesis, highlighting this pathway as a potential therapeutic target. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive search on PubMed, Embase, MEDLINE, and Web of Science databases on June 5, 2024. The search included terms related to Th17 cells, IL-17, and keloids. Thirteen studies met the inclusion criteria, comprising basic science and bioinformatic studies focusing on Th17 cells and IL-17. Key findings include increased Th17 cell infiltration and IL-17 expression in keloids, IL-17's role in amplifying the inflammatory and fibrotic response via the promotion of IL-6 expression, and IL-17's involvement in upregulating fibrotic markers via SDF-1 and HIF-1α pathways. IL-17 also activates the transforming growth factor beta (TGF-ß)/Smad pathway in keloid fibroblasts. Th17 cells and IL-17 significantly contribute to the inflammatory and fibrotic processes in keloid pathogenesis. Therefore, targeting the IL-17 pathway offers a potential new therapeutic target to improve keloid patients' outcomes. Future research could further elucidate the role of Th17 cells and IL-17 in keloid pathogenesis and assess the safety and efficacy of targeting this pathway in human studies.
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Interleucina-17 , Queloide , Células Th17 , Humanos , Queloide/inmunología , Queloide/patología , Células Th17/inmunología , Interleucina-17/metabolismo , Interleucina-17/inmunología , Transducción de Señal/inmunología , Piel/patología , Piel/inmunologíaRESUMEN
In a previous study, it has been shown that the population of Th17 lymphocytes was increased in patients with FMF. IL-21 and IL-23 play significant roles in the production and differentiation of Th17 cells. In this study, we aimed to evaluate serum levels of IL-21 and IL-23 in FMF patients both at diagnosis and after treatment, and to compare these levels with those of healthy controls. Twenty-seven newly diagnosed patients with FMF in attack-free periods and twenty-seven healthy volunteers enrolled in the study. The groups were comparable with respect to age and gender. IL-21 and IL-23 levels in serum samples from patients at the time of diagnosis, in remission after treatment, and from the control groups were analysed using the ELISA method. There was no significant difference between the cytokine levels of the patient group at the time of diagnosis and the cytokine levels of the control group (for IL-21, p: 0.28 and for IL-23, p: 0.56). Similarly, there was no significant difference between the patients' cytokine levels at the time of diagnosis and after treatment (for IL-21, p: 0.99 and for IL-23, p: 0.08). Interleukin levels at the time of diagnosis did not differ among patient groups based on the presence of clinical findings or the M694V genotype. Our results suggest that IL-21 and IL-23 do not play a role in the pathogenesis of the disease. However, while interpreting these findings, it should be considered that patients with active episodes were excluded and cytokine levels were not measured in tissue samples.
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Fiebre Mediterránea Familiar , Interleucina-23 , Interleucinas , Humanos , Femenino , Masculino , Fiebre Mediterránea Familiar/sangre , Fiebre Mediterránea Familiar/tratamiento farmacológico , Fiebre Mediterránea Familiar/inmunología , Interleucinas/sangre , Interleucina-23/sangre , Adulto , Adulto Joven , Estudios de Casos y Controles , Células Th17/inmunología , Células Th17/metabolismo , Citocinas/sangreRESUMEN
BACKGROUND: Systemic lupus erythematosus (SLE) is the quintessential autoimmune disease, as it is characterized by hyperactivity of CD4+ T cells and subsequently drives lupus pathology. Follicular helper T (TFH) cells play an important role in B cell maturation and antibody production. However, which specific subset of cTFH cells drives B cell function and contributes to the development of anti-dsDNA antibodies and SLE pathogenesis remains unclear. METHODS: Peripheral blood mononuclear cells from SLE patients with inactive (n = 11) and active (n = 21) were used to determine and detect frequencies and phenotypes of circulating TFH cells (cTFH), memory cTFH, and B cell subsets. The correlations among cTFH cell subsets and phenotypes, B cell subsets, anti-dsDNA autoantibodies, and clinical parameters were analyzed. RESULTS: In subjects with active SLE, cTFH1 and cTFH17 cells were significantly expanded and activated. These expanded cTFH cells expressed memory phenotypes; cTFH1 cells were predominantly central memory (CM) type, while cTFH17 cells were largely effector memory (EM) type. Phenotyping B cell subsets in these patients showed increased frequencies of aNAV and DN2 B cells. Clinically, ICOS+ cTFH1, ICOS+ cTFH17 cells, and SLEDAI-2k scores were found to be correlated. Analysis of cTFH-B cell relationship revealed positive correlations among ICOS+ cTFH1 cells, aNAV B cells, and anti-dsDNA antibodies. Activation of ICOS+ cTFH17 cells was significantly related to the expansion of aNAV and DN2 B cells. The presence of CM cells in cTFH1 and cTFH17 subsets was correlated with aNAV and DN2 B cell frequencies. CONCLUSION: SLE cTFH cells were found to be polarized toward cTFH1 and cTFH17 cells; activation of these cTFH subsets was significantly associated with disease activity score, aNAV, DN2 B cell expansion, and anti-dsDNA antibody level. Thus, the interactions among cTFH1, cTFH17, and B cells likely contribute to the development of autoantibodies and the pathogenesis in SLE.
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Lupus Eritematoso Sistémico , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/sangre , Femenino , Adulto , Masculino , Persona de Mediana Edad , Linfocitos B/inmunología , Activación de Linfocitos/inmunología , Células T Auxiliares Foliculares/inmunología , Células Th17/inmunología , Adulto Joven , Anticuerpos Antinucleares/inmunología , Anticuerpos Antinucleares/sangreRESUMEN
BACKGROUND: Bone regeneration is a well-regulated dynamic process, of which the prominent role of the immune system on bone homeostasis is more and more revealed by recent research. Before fully activation of the bone remodeling cells, the immune system needs to clean up the microenvironment in facilitating the bone repair initiation. Furthermore, this microenvironment must be maintained properly by various mechanisms over the entire bone regeneration process. OBJECTIVE: This review aims to summarize the role of the T-helper 17/Regulatory T cell (Th17/Treg) balance in bone cell remodeling and discuss the relevant progress in bone tissue engineering. RESULTS: The role of the immune response in the early stages of bone regeneration is crucial, especially the impact of the Th17/Treg balance on osteoclasts, mesenchymal stem cells (MSCs), and osteoblasts activity. By virtue of these knowledge advancements, innovative approaches in bone tissue engineering, such as nano-structures, hydrogel, and exosomes, are designed to influence the Th17/Treg balance and thereby augment bone repair and regeneration. CONCLUSION: Targeting the Th17/Treg balance is a promising innovative strategy for developing new treatments to enhance bone regeneration, thus offering potential breakthroughs in bone injury clinics.
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Regeneración Ósea , Huesos , Linfocitos T Reguladores , Células Th17 , Ingeniería de Tejidos , Humanos , Linfocitos T Reguladores/inmunología , Ingeniería de Tejidos/métodos , Regeneración Ósea/inmunología , Animales , Células Th17/inmunología , Huesos/inmunología , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Remodelación Ósea/inmunología , Osteoblastos/inmunología , Osteoclastos/inmunología , Osteoclastos/metabolismoRESUMEN
The human body harbors a substantial population of bacteria, which may outnumber host cells. Thus, there are multiple interactions between both cell types. Given the common presence of Staphylococcus aureus in the human body and the role of Th17 cells in controlling this pathogen on mucous membranes, we sought to investigate the effect of α-hemolysin, which is produced by this bacterium, on differentiating Th17 cells. RNA sequencing analysis revealed that α-hemolysin influences the expression of signature genes for Th17 cells as well as genes involved in epigenetic regulation. We observed alterations in various histone marks and genome methylation levels via whole-genome bisulfite sequencing. Our findings underscore how bacterial proteins can significantly influence the transcriptome, epigenome, and phenotype of human Th17 cells, highlighting the intricate and complex nature of the interaction between immune cells and the microbiota.
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Toxinas Bacterianas , Epigénesis Genética , Proteínas Hemolisinas , Staphylococcus aureus , Células Th17 , Staphylococcus aureus/inmunología , Staphylococcus aureus/genética , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/inmunología , Proteínas Hemolisinas/metabolismo , Humanos , Células Th17/inmunología , Células Th17/metabolismo , Toxinas Bacterianas/inmunología , Toxinas Bacterianas/genética , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Metilación de ADN , Diferenciación Celular , TranscriptomaRESUMEN
Introduction: After mild COVID-19 that does not require hospitalization, some individuals develop persistent symptoms that may worsen over time, producing a multisystemic condition termed Post-COVID condition (PCC). Among other disorders, PCC is characterized by persistent changes in the immune system that may not be solved several months after COVID-19 diagnosis. Methods: People with PCC were recruited to determine the distribution and functionality of CD4+ T helper (Th) subsets in comparison with individuals with mild, severe, and critical presentations of acute COVID-19 to evaluate their contribution as risk or protective factors for PCC. Results: People with PCC showed low levels of Th1 cells, similar to individuals with severe and critical COVID-19, although these cells presented a higher capacity to express IFNγ in response to stimulation. Th2/Th1 correlation was negative in individuals with acute forms of COVID-19, but there was no significant Th2/Th1 correlation in people with PCC. Th2 cells from people with PCC presented high capacity to express IL-4 and IL-13, which are related to low ventilation and death associated with COVID-19. Levels of proinflammatory Th9 and Th17 subsets were significantly higher in people with PCC in comparison with acute COVID-19, being Th1/Th9 correlation negative in these individuals, which probably contributed to a more pro-inflammatory than antiviral scenario. Th17 cells from approximately 50% of individuals with PCC had no capacity to express IL-17A and IL-22, similar to individuals with critical COVID-19, which would prevent clearing extracellular pathogens. Th2/Th17 correlation was positive in people with PCC, which in the absence of negative Th1/Th2 correlation could also contribute to the proinflammatory state. Finally, Th22 cells from most individuals with PCC had no capacity to express IL-13 or IL-22, which could increase tendency to reinfections due to impaired epithelial regeneration. Discussion: People with PCC showed skewed polarization of CD4+ Th subsets with altered functionality that was more similar to individuals with severe and critical presentations of acute COVID-19 than to people who fully recovered from mild disease. New strategies aimed at reprogramming the immune response and redirecting CD4+ Th cell polarization may be necessary to reduce the proinflammatory environment characteristic of PCC.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/inmunología , Masculino , Femenino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Anciano , Adulto , Células TH1/inmunología , Células Th2/inmunología , Linfocitos T CD4-Positivos/inmunología , Síndrome Post Agudo de COVID-19 , Citocinas/metabolismo , Citocinas/inmunología , Células Th17/inmunología , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Mesenchymal stromal/stem cells (MSC) have emerged as a promising therapeutic avenue for treating autoimmune diseases, eliciting considerable interest and discussion regarding their underlying mechanisms. This study revealed the distinctive ability of human umbilical cord MSC to aggregate within the lymph nodes of mice afflicted with autoimmune diseases, but this phenomenon was not observed in healthy mice. The specific distribution is driven by the heightened expression of the CCL21-CCR7 axis in mice with autoimmune diseases, facilitating the targeted homing of MSC to the lymph nodes. Within the lymph nodes, MSC exhibit a remarkable capacity to modulate Th17 cell function, exerting a pronounced anti-inflammatory effect. Transplanted MSC stimulates the secretion of L-amino-acid oxidase (LAAO), a response triggered by elevated levels of tumor necrosis factor-α (TNF-α) in mice with autoimmune diseases through the NF-κB pathway. The presence of LAAO is indispensable for the efficacy of MSC, as it significantly contributes to the inhibition of Th17 cells. Furthermore, LAAO-derived indole-3-pyruvic acid (I3P) serves as a potent suppressor of Th17 cells by activating the aryl hydrocarbon receptor (AHR) pathway. These findings advance our understanding of the global immunomodulatory effects exerted by MSC, providing valuable information for optimizing therapeutic outcomes.
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L-Aminoácido Oxidasa , Ganglios Linfáticos , Células Madre Mesenquimatosas , Células Th17 , Animales , Células Madre Mesenquimatosas/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , L-Aminoácido Oxidasa/metabolismo , Ganglios Linfáticos/metabolismo , Ratones , Humanos , Ratones Endogámicos C57BL , Receptores CCR7/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Receptores de Hidrocarburo de Aril/genética , FN-kappa B/metabolismo , Trasplante de Células Madre Mesenquimatosas , Transducción de Señal , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Factor de Necrosis Tumoral alfa/metabolismo , Quimiocina CCL21/metabolismoRESUMEN
The aim of this study was to elucidate the therapeutic effect of simvastatin on experimental autoimmune encephalomyelitis (EAE) by regulating the balance between Th17 and Treg cells in mice. C57BL/6 mice were randomly divided into four groups: normal group, EAE group, simvastatin (2 and 10 mg/kg) group, and AG490 group (with AG490 serving as the positive control). Neurological function scores of mice were assessed daily. The four groups received treatments of normal saline, normal saline, and simvastatin (2 and 10 mg/kg), respectively. In the AG490 group, mice were injected intraperitoneally with AG490 (1 mg) every other day, and treatment was halted after 3 weeks. The spinal cord was stained with hematoxylin and eosin (H&E), and immunohistochemical staining for retinoic acid receptor-related orphan receptor γ(RORγ) and Foxp3 (Foxp3) was performed. Spleen samples were taken for Th17 and Treg analysis using flow cytometry. The levels of interleukin-17 and transforming growth factor-ß (TGF-ß) were detected using enzyme-linked immunosorbent assay (ELISA). In the simvastatin and AG490 groups, recovery from neurological impairment was earlier compared to the EAE group, and the symptoms were notably improved. Both simvastatin and AG490 reduced focal inflammation, decreased RORγ-positive cell infiltration, and significantly increased the number of FOXP3-positive cells. The number of Th17 cells and the level of IL-17 in the spleen were decreased in the simvastatin and AG490 treatment groups, while the number of Treg cells and TGF-ß levels were significantly increased across all treatment groups. Simvastatin exhibits anti-inflammatory and immunomodulatory effects, potentially alleviating symptoms of neurological dysfunction of EAE. Regulating the balance between Th17 and Treg may represent a therapeutic mechanism for simvastatin in treating EAE.
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Encefalomielitis Autoinmune Experimental , Ratones Endogámicos C57BL , Simvastatina , Linfocitos T Reguladores , Células Th17 , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Células Th17/inmunología , Células Th17/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Simvastatina/farmacología , Simvastatina/administración & dosificación , Ratones , Femenino , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Interleucina-17/metabolismo , Factores de Transcripción Forkhead/metabolismo , Médula Espinal/inmunología , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Humanos , Factor de Crecimiento Transformador beta/metabolismo , Modelos Animales de EnfermedadRESUMEN
Multiple lines of evidence suggest that Retinoic Acid Related Orphan Nuclear Receptor gamma t (RORγt) is a potent therapeutic target for inflammatory bowel disease (IBD). However, systemic blockade of RORγt easily leads to thymic lymphoma and aberrant liver function. Therefore, the development of gut-limited RORγt antagonists may lead to the development of innovative IBD therapeutics that improve safety and retain effectiveness. We discovered SPH7854, a potent and selective RORγt antagonist. The effect of SPH7854 on the differentiation of T helper 1 (Th1)/Th17/regulatory T (Treg) cells was evaluated in mouse and human primary cells. SPH7854 (2-(4-(ethylsulfonyl)phenyl)-N- (6-(2-methyl-2-(pyridin-2-yl) propanoyl)pyridin-3-yl)acetamide) dose-dependently inhibited interleukin-17A (IL-17A) secretion from mouse CD4 + T cells and human peripheral blood mononuclear cells (PBMC). Additionally, SPH7854 strongly suppressed Th17 cell differentiation and considerably promoted Treg cell differentiation while slightly affected Th1 cell differentiation from mouse CD4 + T cells. The pharmacokinetic (PK) studies indicated that SPH7854 was restricted to the gut: the bioavailability and maximal plasma concentration of SPH7854 after oral administration (6 mg/kg) were 1.24 ± 0.33 % and 4.92 ± 11.81 nM, respectively, in rats. Strikingly, oral administration of SPH7854 (5 mg/kg and 15 mg/kg) twice daily significantly alleviated 2, 4, 6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. SPH7854, especially at 15 mg/kg, significantly alleviated symptoms and improved macroscopic signs and microscopic structure in rat colitis, with decreased colonic mucosal levels of IL-17A, IL-6, tumor necrosis factor α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and myeloperoxidase (MPO). These evidences indicated that blockade of RORγt activity via a gut-limited antagonist may be an effective and safe therapeutic strategy for IBD treatment.
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Colitis , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Células Th17 , Ácido Trinitrobencenosulfónico , Animales , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Humanos , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/inmunología , Masculino , Ratas , Ratones , Células Th17/inmunología , Células Th17/efectos de los fármacos , Ratas Sprague-Dawley , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Interleucina-17/metabolismo , Interleucina-17/antagonistas & inhibidores , Acetamidas/uso terapéutico , Acetamidas/farmacología , Células Cultivadas , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Colon/efectos de los fármacos , Colon/patología , Colon/inmunología , Ratones Endogámicos C57BLRESUMEN
Th1 and Th2 cytokines determine the outcome of Leishmania major infection and immune protection depends mainly on memory T cells induced during vaccination. This largely hinges on the nature and type of memory T cells produced. In this study, transgenic Leishmania major strains expressing membrane-associated ovalbumin (mOVA) and soluble ovalbumin (sOVA) were used as a model to study whether fully differentiated Th1/Th2 and Th17 cells can recall immune memory and tolerate pathogen manipulation. Naïve OT-II T cells were polarised in vitro into Th1/Th2 cells, and these cells were transferred adoptively into recipient mice. Following the transferral of the memory cells, the recipient mice were challenged with OVA transgenic Leishmania major and a wild-type parasite was used a control. The in vitro-polarised T helper cells continued to produce the same cytokine signatures after being challenged by both forms of OVA-expressing Leishmania major parasites in vivo. This suggests that antigen-experienced cells remain the same or unaltered in the face of OVA-transgenic Leishmania major. Such ability of these antigen-experienced cells to remain resilient to manipulation by the parasite signifies that vaccines might be able to produce immune memory responses and defend against parasitic immune manipulation in order to protect the host from infection.
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Memoria Inmunológica , Leishmania major , Ovalbúmina , Células TH1 , Células Th17 , Células Th2 , Animales , Leishmania major/inmunología , Ovalbúmina/inmunología , Ratones , Células TH1/inmunología , Células Th2/inmunología , Células Th17/inmunología , Citocinas/metabolismo , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/parasitología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Femenino , Ratones TransgénicosRESUMEN
BACKGROUND: Postinfectious Lyme arthritis (LA) is associated with dysregulated immunity and autoreactive T- and B-cell responses in joints. Here we explored the role of host genetic variation in this outcome. METHODS: The frequency of 253 702 single-nucleotide polymorphisms (SNPs) was determined in 147 patients with LA (87 with postinfectious LA and 60 with antibiotic-responsive LA), and for comparison in 90 patients with erythema migrans or the general population (n = 2504). Functional outcome of candidate SNPs was assessed by evaluating their impact on clinical outcome and on immune responses in blood and synovial fluid in patients with LA. RESULTS: Six SNPs associated with late cornified envelope (LCE3) genes were present at greater frequency in patients with postinfectious LA compared to those with antibiotic-responsive LA (70% vs 30%; odds ratio, 2; P < .01). These SNPs were associated with heightened levels of inflammatory Th17 cytokines in serum but lower levels of interleukin 27, a regulatory cytokine, implying that they may contribute to dysregulated Th17 immunity in blood. Moreover, in patients with postinfectious LA, the levels of these Th17 mediators correlated directly with autoantibody responses in synovial fluid, providing a possible link between LCE3 SNPs, maladaptive systemic Th17 immunity, and autoreactive responses in joints. CONCLUSIONS: Variation in the LCE3 locus, a known genetic risk factor in psoriasis and psoriatic arthritis, is associated with dysregulated systemic Th17 immunity and heightened autoantibody responses in joints. These findings underscore the importance of host genetic predisposition and systemic Th17 immunity in the pathogenesis of postinfectious (antibiotic-refractory) Lyme arthritis.
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Enfermedad de Lyme , Polimorfismo de Nucleótido Simple , Células Th17 , Humanos , Enfermedad de Lyme/genética , Enfermedad de Lyme/inmunología , Células Th17/inmunología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Líquido Sinovial/inmunología , Anciano , Citocinas/genética , Citocinas/metabolismo , Artritis Infecciosa/genética , Artritis Infecciosa/inmunología , Adulto JovenRESUMEN
Formyl peptide receptor 2 (FPR2) is a receptor for formylated peptides and specific pro-resolving mediators, and is involved in various inflammatory processes. Here, we aimed to elucidate the role of FPR2 in dendritic cell (DC) function and autoimmunity-related central nervous system (CNS) inflammation by using the experimental autoimmune encephalomyelitis (EAE) model. EAE induction was accompanied by increased Fpr2 mRNA expression in the spinal cord. FPR2-deficient (Fpr2 KO) mice displayed delayed onset of EAE compared to wild-type (WT) mice, associated with reduced frequencies of Th17 cells in the inflamed spinal cord at the early stage of the disease. However, FPR2 deficiency did not affect EAE severity after the disease reached its peak. FPR2 deficiency in mature DCs resulted in decreased expression of Th17 polarizing cytokines IL6, IL23p19, IL1ß, and thereby diminished the DC-mediated activation of Th17 cell differentiation. LPS-activated FPR2-deficient DCs showed upregulated Nos2 expression and nitric oxide (NO) production, as well as reduced oxygen consumption rate and impaired mitochondrial function, including decreased mitochondrial superoxide levels, lower mitochondrial membrane potential and diminished expression of genes related to the tricarboxylic acid cycle and genes related to the electron transport chain, as compared to WT DCs. Treatment with a NO inhibitor reversed the reduced Th17 cell differentiation in the presence of FPR2-deficient DCs. Together, by regulating DC metabolism, FPR2 enhances the production of DC-derived Th17-polarizing cytokines and hence Th17 cell differentiation in the context of neuroinflammation.
Asunto(s)
Diferenciación Celular , Células Dendríticas , Encefalomielitis Autoinmune Experimental , Ratones Noqueados , Receptores de Formil Péptido , Células Th17 , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Receptores de Formil Péptido/genética , Receptores de Formil Péptido/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Ratones , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Ratones Endogámicos C57BL , Citocinas/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Femenino , Médula Espinal/inmunología , Médula Espinal/metabolismoRESUMEN
While Resolvin D1 (RvD1) shows promise in resolving inflammation in experimental autoimmune encephalomyelitis (EAE), its pro-resolving roles on dendritic cells (DCs) remain unknown, and the chemical instability of RvD1 poses significant challenges to its drug development. This study aims to investigate whether 4-(2'-methoxyphenyl)-1-[2'-[N-(2â³-pyridinyl)-p-fluorobenzamido]ethyl]piperazine (p-MPPF), a novel chemically stable analogue of RvD1, can play a pro-resolving role in EAE, particularly on DCs, and if p-MPPF could serve as a potential substitute for RvD1. We showed that both RvD1 and p-MPPF mediated the resolution of inflammation in EAE, as evidenced by ameliorated EAE progression, attenuated pathological changes in the spinal cord, altered cytokine expression profile in serum, and reduced proportion of pro-inflammatory immune cells in the spleen. Utilizing DCs derived from both the spleen and bone marrow of EAE, our investigation showed that RvD1 and p-MPPF prevented DC maturation, decreased pro-inflammatory cytokine secretion, shifted DCs away from a pro-inflammatory phenotype, increased the phagocytosis capacity of DCs, and suppressed their ability to induce differentiation of CD4+ T cells into Th1 and Th17 subsets. For underlying intracellular mechanisms, we found that RvD1 and p-MPPF down-regulated the lactate dehydrogenase A signaling pathways. Comparisons between RvD1 and p-MPPF showed that they exerted overlapped pro-resolving effects to a large extent. This study demonstrates that both RvD1 and p-MPPF exert therapeutic effects on EAE by mediating inflammation resolution, which is closely associated with modulating DC immune function towards a tolerogenic phenotype. SPM mimetics may serve as a more promising therapeutic drug.
Asunto(s)
Citocinas , Células Dendríticas , Ácidos Docosahexaenoicos , Encefalomielitis Autoinmune Experimental , Ratones Endogámicos C57BL , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/inmunología , Animales , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Ácidos Docosahexaenoicos/uso terapéutico , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/química , Femenino , Ratones , Citocinas/metabolismo , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/patología , Médula Espinal/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Piperazinas/farmacología , Piperazinas/uso terapéutico , Piperazinas/química , Células Cultivadas , Bazo/efectos de los fármacos , Bazo/inmunología , Células Th17/inmunología , Células Th17/efectos de los fármacosRESUMEN
Psoriasis is an autoinflammatory dermatosis, while methotrexate (MTX) is an immunosuppressant used to treat psoriasis. However, conventional immunosuppressants may cause various side effects. Acupuncture has potential benefits in treating psoriasis based on its anti-inflammatory effects. However, the immune mechanisms underlying its effects remain unclear. In this study, imiquimod-induced psoriatic mice were used to investigate the effects and mechanisms of electroacupuncture (EA) and, in particular, its joint treatment with MTX. We found that treatment with either EA or MTX ameliorated psoriasiform skin lesions, improved skin pathology and reduced proinflammatory cytokines in the skin, while joint treatment with both EA and MTX further alleviated the skin lesions and inflammation compared to either one alone. Moreover, percentages of CD4+ IL-17A+ Th17 cells in the skin and lymph nodes were decreased by EA or MTX and further lowered by combined EA+MTX treatment. Similarly, EA or MTX also reduced their RORγt expression. On the contrary, CD4+ FoxP3+ Treg frequency in psoriatic mice was augmented by EA or MTX and further increased by the joint treatment. However, depleting Tregs mostly reversed the therapeutic effects of EA or EA plus MTX. Additionally, the phosphorylated NF-κB (p65) expression was suppressed by treatment with EA, MTX or better with EA+MTX. Meanwhile, the anti-inflammatory effects of EA plus MTX were offset by an NF-κB agonist. Thus, this study has revealed that EA cooperates with MTX to balance Th17/Treg responses and to ameliorate psoriasiform skin inflammation through suppressing NF-κB activation. Our findings may be implicated for treating human psoriasis.
Asunto(s)
Electroacupuntura , Imiquimod , Metotrexato , Psoriasis , Piel , Linfocitos T Reguladores , Células Th17 , Animales , Psoriasis/inmunología , Psoriasis/tratamiento farmacológico , Psoriasis/terapia , Psoriasis/inducido químicamente , Células Th17/inmunología , Células Th17/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Electroacupuntura/métodos , Piel/patología , Piel/efectos de los fármacos , Piel/inmunología , Ratones , Modelos Animales de Enfermedad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Humanos , FN-kappa B/metabolismo , Terapia Combinada , Masculino , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismoRESUMEN
Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects.
Asunto(s)
Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-1 , Neoplasias Pancreáticas , Esfingomielinas , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Humanos , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucina-1/metabolismo , Esfingomielinas/metabolismo , Citocinas/metabolismo , Línea Celular Tumoral , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Células Th17/inmunología , Células Th17/efectos de los fármacos , Células Th17/metabolismo , Células Th2/inmunología , Células Th2/efectos de los fármacos , Células Th2/metabolismo , Microambiente Tumoral/efectos de los fármacos , Nanopartículas/química , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/efectos de los fármacosRESUMEN
Neuroimmune cross-talk participates in intestinal tissue homeostasis and host defense. However, the matrix of interactions between arrays of molecularly defined neuron subsets and of immunocyte lineages remains unclear. We used a chemogenetic approach to activate eight distinct neuronal subsets, assessing effects by deep immunophenotyping, microbiome profiling, and immunocyte transcriptomics in intestinal organs. Distinct immune perturbations followed neuronal activation: Nitrergic neurons regulated T helper 17 (TH17)-like cells, and cholinergic neurons regulated neutrophils. Nociceptor neurons, expressing Trpv1, elicited the broadest immunomodulation, inducing changes in innate lymphocytes, macrophages, and RORγ+ regulatory T (Treg) cells. Neuroanatomical, genetic, and pharmacological follow-up showed that Trpv1+ neurons in dorsal root ganglia decreased Treg cell numbers via the neuropeptide calcitonin gene-related peptide (CGRP). Given the role of these neurons in nociception, these data potentially link pain signaling with gut Treg cell function.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina , Ganglios Espinales , Neuroinmunomodulación , Nociceptores , Linfocitos T Reguladores , Canales Catiónicos TRPV , Células Th17 , Animales , Ratones , Péptido Relacionado con Gen de Calcitonina/metabolismo , Péptido Relacionado con Gen de Calcitonina/genética , Neuronas Colinérgicas/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/citología , Microbioma Gastrointestinal , Intestinos/inmunología , Intestinos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Nocicepción , Nociceptores/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/inmunología , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genéticaRESUMEN
The establishment and maintenance of a successful pregnancy rely heavily on maternal-fetal immune tolerance. Inflammatory and immune mechanisms during pregnancy bear a resemblance to those observed in tumor progression, with Treg cells exhibiting similar immunoregulatory functions in both contexts. Interferon regulatory factor 1 (IRF1) is implicated in modulating the immune milieu within tumors and influencing regulatory T (Treg) cell differentiation. However, the precise association between IRF1 and the onset of preeclampsia (PE) remains unclear. In our investigation, we identified trophoblasts as a significant source of IRF1 expression at the maternal-fetal interface through immunofluorescence analysis. Moreover, heightened levels of IRF1 expression were detected in both placental tissues and peripheral blood samples obtained from PE patients, concomitant with an imbalance in the Th17/Treg ratio. In the peripheral circulation, a notable inverse correlation was observed between IRF1 mRNA levels and Foxp3 mRNA, a transcription factor specific to Treg cells. IRF1 mRNA expression showed a positive association with systolic blood pressure and a negative association with serum albumin levels. Furthermore, co-culturing naïve T cells with supernatants from HTR-8/SV neo cells overexpressing IRF1 resulted in diminished differentiation of T cells into Treg cells. In summary, our study indicates elevated IRF1 expression in the peripheral blood and trophoblast cells of PE patients. Elevated IRF1 in trophoblast cells hinders the differentiation of maternal Treg cells, disrupting maternal-fetal immune tolerance and contributing to PE pathogenesis. Additionally, IRF1 expression correlates with disease severity, suggesting its potential as a novel sensitive target in PE.