RESUMO
OBJECTIVE: The use of biologic agents, mainly tumor necrosis factor (TNF)-α and interleukin (IL)-17A inhibitors, was associated with cutaneous side effects, but the factors associated with eczematous reactions occurring during biologic treatments are not completely known. PATIENTS AND METHODS: An observational, retrospective, multicentre Italian study evaluated the clinical features and the management of eczematous eruptions in 54 patients with chronic plaque psoriasis who developed eczema after treatment with biological agents (anti-IL-17 or 23). RESULTS: Many of these patients had personal and family history of atopy. Eczematous reactions developed between a few days and 3 years after initiation of the biologic drug. The highest proportion of cases associated with eczematous reactions during biologic treatments was seen in patients on anti-IL-17 agents, including brodalumab. We observed that eczema rapidly remitted without relapse in all patients who switched to anti-IL-23 agents. Among our cases, fast responders to psoriasis therapy seem to have more persistent eczematous reactions. CONCLUSIONS: Patients with psoriasis and a history of atopic dermatitis should be treated with an IL-23 inhibitor due to its efficacy in psoriasis and the rarely reported eczematous reaction.
Assuntos
Eczema , Psoríase , Humanos , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , Estudos Retrospectivos , Eczema/induzido quimicamente , Eczema/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Interleucina-17/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/efeitos adversos , Terapia Biológica/efeitos adversos , Interleucina-23/antagonistas & inibidoresRESUMO
BACKGROUND: Endothelial dysfunction is an integral pathophysiologic mechanism in sickle cell disease (SCD), and can lead to many complications. Sleep-disordered breathing (SDB) is a SCD complication with diverse incidence and pathophysiology. This study aimed to determine the prevalence of SDB in children with SCD and to assess its relation to endothelial dysfunction. METHODS: Sixty children with SCD and 60 healthy controls were enrolled. The levels of TNF-α, IL-6, and IL-17A were evaluated in the entire cohort using enzyme-linked immunosorbent assay (ELISA) kits. Polysomnography (PSG) was performed for all SCD patients after completion of the Pediatric Sleep Questionnaire (PSQ). RESULTS: TNF-α, IL-6, and IL-17A levels were significantly greater in children with SCD than in controls (p-values < 0.001, < 0.001, and 0.006, respectively). The PSQ revealed symptoms suggestive of SDB in 50 children with SCD (83.3%), and PSG revealed obstructive sleep apnea (OSA) in 44 children with SCD (73.3%); 22 patients had mild OSA, and 22 had moderate-to-severe OSA according to the apnea-hypopnea index (AHI). TNF-α was significantly greater in SCD children who reported heavy or loud breathing, trouble breathing or struggle to breathe, and difficulty waking up in the morning (p-values = 0.002, 0.002, and 0.031, respectively). The IL-6 levels were significantly greater in SCD children who stopped growing normally (p-value = 0.002). The levels of IL-6 and IL-17A were significantly greater in SCD children with morning headaches (p-values = 0.007 and 0.004, respectively). CONCLUSION: Children with SCD showed a high prevalence of SDB with significantly elevated levels of markers of endothelial function, highlighting the interplay of SDB and endothelial dysfunction in SCD.
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Anemia Falciforme , Endotélio Vascular , Interleucina-6 , Polissonografia , Síndromes da Apneia do Sono , Fator de Necrose Tumoral alfa , Humanos , Anemia Falciforme/complicações , Anemia Falciforme/fisiopatologia , Masculino , Feminino , Criança , Síndromes da Apneia do Sono/fisiopatologia , Síndromes da Apneia do Sono/epidemiologia , Síndromes da Apneia do Sono/complicações , Egito/epidemiologia , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangue , Estudos de Casos e Controles , Endotélio Vascular/fisiopatologia , Interleucina-17/sangue , Prevalência , Adolescente , Biomarcadores/sangue , Estudos TransversaisRESUMO
As potent pro-inflammatory mediators, IL-17 family cytokines play crucial roles in the pathogenesis of various inflammatory and autoimmune skin disorders. Although substantial progress has been achieved in understanding the pivotal role of IL-17A signaling in psoriasis, leading to the development of highly effective biologics, the functions of other IL-17 family members in inflammatory or autoimmune skin diseases remain less explored. In this review, we provide a comprehensive overview of IL-17 family cytokines and their receptors, with a particular focus on the recent advancements in identifying cellular sources, receptors and signaling pathways regulated by these cytokines. At the end, we discuss how the aberrant functions of IL-17 family cytokines contribute to the pathogenesis of diverse inflammatory or autoimmune skin diseases.
Assuntos
Doenças Autoimunes , Interleucina-17 , Transdução de Sinais , Dermatopatias , Humanos , Interleucina-17/metabolismo , Interleucina-17/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Animais , Dermatopatias/imunologia , Dermatopatias/metabolismo , Psoríase/imunologia , Psoríase/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-17/imunologiaRESUMO
BACKGROUND: Neurogenic erectile dysfunction, characterized by neurological repair disorders and progressive corpus cavernosum fibrosis (CCF), is an unbearable disease with limited treatment success. IL-17A exhibits a complex role in tissue remodelling. Nevertheless, the precise role and underlying mechanisms of IL-17A in CCF under denervation remain unclear. METHODS: PCR array was employed to identified differentially expressed genes between neurogenic ED and normal rats. IL-17A expression and its main target cells were analyzed using Western blotting, immunofluorescence and immunohistochemistry. The phenotypic regulation of IL-17A on corpus cavernosum smooth muscle cells (CSMCs) was evaluated by cell cycle experiments and SA-ß-Gal staining. The mechanism of IL-17A was elucidated using non-target metabolomics and siRNA technique. Finally, IL-17A antagonist and ABT-263 (an inhibitor of B-cell lymphoma 2/w/xL) were utilized to enhance the therapeutic effect in a rat model of neurogenic ED. RESULTS: IL-17A emerged as the most significantly upregulated gene in the corpus cavernosum of model rats. It augmented the senescence transformation and fibrotic response of CSMCs, and exhibited a strong correlation with CCF. Mechanistically, IL-17A facilitated CCF by activating the mTORC2-ACACA signalling pathway, upregulating of CSMCs lipid synthesis and senescence transition, and increasing the secretion of fibro-matrix proteins. In vivo, the blockade of IL-17A-senescence signalling improved erectile function and alleviated CCF in neurogenic ED. CONCLUSIONS: IL-17A assumes a pivotal role in denervated CCF by activating the mTORC2-ACACA signalling pathway, presenting itself as a potential therapeutic target for effectively overcoming CCF and erection rehabilitation in neurogenic ED.
Assuntos
Disfunção Erétil , Fibrose , Interleucina-17 , Pênis , Transdução de Sinais , Animais , Masculino , Disfunção Erétil/tratamento farmacológico , Interleucina-17/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Pênis/inervação , Pênis/patologia , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Ratos Sprague-Dawley , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
Background: To effectively control tuberculosis (TB), it is crucial to distinguish between active TB disease and latent TB infection (LTBI) to provide appropriate treatment. However, no such tests are currently available. Immune responses associated with active TB and LTBI are dynamic and exhibit distinct patterns. Comparing these differences is crucial for developing new diagnostic methods and understanding the etiology of TB. This study aimed to investigate the relationship between pro- and anti-inflammatory CD4+ cytokine production following stimulation with two types of latency-associated Mycobacterium tuberculosis (M.tb) antigens to allow differentiation between active TB and LTBI. Methods: Cryopreserved PBMCs from patients with active TB disease or LTBI were stimulated overnight with replication-related antigen [ESAT-6/CFP-10 (E/C)] or two latency-associated antigens [heparin-binding hemagglutinin (HBHA) and alpha-crystallin-like protein (Acr)]. Responses were analyzed using multiparameter flow cytometry: active TB disease (n=15), LTBI (n=15) and ELISA: active TB disease (n=26) or LTBI (n=27). Results: CD4+ central memory T cells (Tcm) specific to E/C and CD4+ effector memory T cells specific to Acr and HBHA were higher in LTBI than in TB patients. IFN-γ+Tcm and IL-17+ Tem cells was higher in the LTBI group (p= 0.012 and p=0.029 respectively), but IL-10+ Tcm was higher in the active TB group (p= 0.029) following HBHA stimulation. Additionally, following stimulation with HBHA, IL-10 production from CD4+ T cells was significantly elevated in patients with active TB compared to those with LTBI (p= 0.0038), while CD4+ T cell production of IL-17 and IFN-γ was significantly elevated in LTBI compared to active TB (p= 0.0076, p< 0.0001, respectively). HBHA also induced more CCR6+IL-17+CD4Tcells and IL-17+FoxP3+CD25+CD4Tcells in LTBI than in TB patients (P=0.026 and P=0.04, respectively). HBHA also induced higher levels of IFN-γ+IL-10+CD4+ T cells in patients with active TB (Pp=0.03) and higher levels of IFN-γ+IL-17+ CD4+ T cells in those with LTBI (p=0.04). HBHA-specific cytokine production measured using ELISA showed higher levels of IFN-γ in participants with LTBI (P=0.004) and higher levels of IL-10 in those with active TB (P=0.04). Conclusion: Stimulation with HBHA and measurement of CD4+ T cell production of IFN-γ, IL-10, and IL-17 could potentially differentiate active TB from LTBI. The characteristics of cytokine-expressing cells induced by HBHA also differed between participants with active TB and LTBI.
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Antígenos de Bactérias , Linfócitos T CD4-Positivos , Interferon gama , Interleucina-10 , Interleucina-17 , Tuberculose Latente , Mycobacterium tuberculosis , Tuberculose , Humanos , Masculino , Feminino , Linfócitos T CD4-Positivos/imunologia , Adulto , Interleucina-17/imunologia , Interleucina-17/metabolismo , Mycobacterium tuberculosis/imunologia , Interleucina-10/imunologia , Interferon gama/metabolismo , Interferon gama/imunologia , Pessoa de Meia-Idade , Tuberculose Latente/imunologia , Tuberculose/imunologia , Antígenos de Bactérias/imunologia , Idoso , Adulto Jovem , LectinasRESUMO
Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer, and its pathogenesis remains not fully elucidated. Inflammation and metabolic dysregulation are considered to play crucial roles in LUAD development, but their causal relationships and specific mechanisms remain unclear. Methods: This study employed a two-sample Mendelian randomization (MR) approach to systematically evaluate the causal associations between 91 circulating inflammatory factors, 1,400 serum metabolites, and LUAD. We utilized LUAD genome-wide association studies (GWAS) data from the FinnGen biobank and GWAS data of metabolites and inflammatory factors from the GWAS catalog to conduct two-sample MR analyses. For the identified key metabolites, we further used mediator MR to investigate their mediating effects in the influence of IL-17A on LUAD and explored potential mechanisms through protein-protein interaction and functional enrichment analyses. Results: The MR analyses revealed that IL-17A (OR 0.78, 95%CI 0.62-0.99) was negatively associated with LUAD, while 71 metabolites were significantly associated with LUAD. Among them, ferulic acid 4-sulfate may play a crucial mediating role in the suppression of LUAD by IL-17A (OR 0.87, 95%CI 0.78-0.97). IL-17A may exert its anti-LUAD effects through extensive interactions with genes related to ferulic acid 4-sulfate metabolism (such as SULT1A1, CYP1A1, etc.), inhibiting oxidative stress and inflammatory responses, as well as downstream tumor-related pathways of ferulic acid 4-sulfate (such as MAPK, NF-κB, etc.). Conclusion: This study discovered causal associations between IL-17A, multiple serum metabolites, and LUAD occurrence, revealing the key role of inflammatory and metabolic dysregulation in LUAD pathogenesis. Our findings provide new evidence-based medical support for specific inflammatory factors and metabolites as early predictive and risk assessment biomarkers for LUAD, offering important clues for subsequent mechanistic studies and precision medicine applications.
Assuntos
Adenocarcinoma de Pulmão , Estudo de Associação Genômica Ampla , Inflamação , Neoplasias Pulmonares , Análise da Randomização Mendeliana , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangue , Inflamação/genética , Inflamação/sangue , Inflamação/metabolismo , Interleucina-17/sangue , Interleucina-17/genética , Fatores de Risco , Polimorfismo de Nucleotídeo ÚnicoRESUMO
We developed a model of inflammation and airway remodeling in C57 mice provoked by exosomes derived from bone marrow mesenchymal stem cells infected by respiratory syncytial virus (RSV). The mean size of control and infected exosomes in vitro were 167.9 and 118.5 nm, respectively. After induction of modeled pathology, the severity of airway inflammation and its remodeling were analyzed by histopathological methods. In addition, the blood levels of inflammatory factors IL-10, IL-17, transforming growth factor-ß (TGF-ß), and TNFα were assayed; in the lung tissues, the expression levels of MMP-2, MMP-9, α-smooth muscle actin (α-SMA), and TGF-ß were measured. In the developed model, the effects of RSV-induced and non-induced exosomes were compared with those of inactivated and non-inactivated RSV. Intranasal administration of RSV-induced exosomes decreased the levels of serum inflammatory factors IL-10 and IL-17 and increased the expression of serum proinflammatory cytokine TNFα. Increased levels of MMP-2, MMP-9, and α-SMA, enhanced expression of TGF-ß in the lung tissue, and pathological staining of the lung tissues indicated infiltration with inflammatory cells and luminal constriction. Thus, RSV-induced exosomes can provoke airway inflammation and remodeling in mice similar to RSV, while non-induced exosomes cannot produce such alterations.
Assuntos
Remodelação das Vias Aéreas , Modelos Animais de Doenças , Exossomos , Interleucina-10 , Interleucina-17 , Metaloproteinase 2 da Matriz , Células-Tronco Mesenquimais , Camundongos Endogâmicos C57BL , Infecções por Vírus Respiratório Sincicial , Fator de Necrose Tumoral alfa , Animais , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Infecções por Vírus Respiratório Sincicial/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/sangue , Interleucina-10/metabolismo , Interleucina-10/sangue , Interleucina-17/metabolismo , Pulmão/patologia , Pulmão/virologia , Pulmão/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Vírus Sinciciais Respiratórios/patogenicidade , Fator de Crescimento Transformador beta/metabolismo , Actinas/metabolismo , Inflamação/patologia , Inflamação/metabolismo , Células da Medula Óssea/metabolismo , FemininoRESUMO
BACKGROUND: The psoriatic arthritis (PsA) Observational Study of Persistence of Treatment (PRO-SPIRIT) assesses effectiveness and persistence of real-world PsA treatments. Ixekizumab (IXE) is an interleukin (IL)-17A inhibitor (i) (IL-17Ai), approved for the treatment of adult PsA. METHODS: The aim of this predefined interim analysis was to report baseline characteristics along with early (3-month) descriptive and comparative real-world effectiveness in patients with PsA prescribed with advanced treatment including IL-17Ai; IXE or secukinumab (SEC), IL-12/23i, IL-23i, tumour necrosis factor (TNFi) or Janus kinase (JAKi). RESULTS: 1192 patients across 6 countries were analysed. At baseline, patients receiving IXE had longer disease duration and higher previous biological/targeted-synthetic disease-modifying antirheumatic drugs experience than patients starting TNFi and SEC 150, and less concomitant conventional-synthetic DMARD use than TNFi and JAKi. Comparative analyses at 3 months showed that: (a) versus TNFi, IXE exhibited similar improvement in clinical Disease Activity in PsA (cDAPSA) but significantly greater improvement in body surface area affected by psoriasis (BSA) and global assessments (physician GA, patient GA (PatGA)); (b) versus IL-12/23i and IL-23i (pooled), IXE showed significantly greater improvement in cDAPSA and PatGA; (c) IXE was as fast as JAKi in improving joint disease activity. Ad hoc analysis indicated that more patients with active psoriasis (BSA ≥3%) achieved minimal disease activity with IXE than JAKi or IL-12/23i. The responses to SEC varied by dosage. CONCLUSIONS: This study confirms the rapid 3-month effectiveness of IXE on joint disease activity-as fast as TNFi and JAKi (cDAPSA), and exceeding IL-12/23i and IL-23i-along with clear benefits to skin.
Assuntos
Anticorpos Monoclonais Humanizados , Artrite Psoriásica , Humanos , Artrite Psoriásica/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto , Antirreumáticos/uso terapêutico , Interleucina-17/antagonistas & inibidores , Interleucina-12/antagonistas & inibidoresRESUMO
OBJECTIVES: To analyze the clinical significance of Toll-Like Receptor 7/Interleukin-23/Interleukin-17 (TLR7/IL-23/IL-17) signaling pathway in patients with Acute Respiratory Distress Syndrome (ARDS). METHOD: The clinical data of 85 patients with ARDS were retrospectively analyzed and set as the ARDS group, and the clinical data of 85 healthy participants during the same period were set as the healthy control group. Univariate and multivariate logistic regression were used to analyze risk the factors affecting the prognosis of ARDS patients. RESULTS: TheTLR7 mRNA expression and IL-23 and IL-17 levels in peripheral blood mononuclear cells were higher in the ARDS group than in the control group (p < 0.05). TLR7 mRNA expression, IL-23, IL-17, Surfactant Protein-D (SP-D), and Clara Cell protein-16 (CC-16) levels were the highest in the severe group, followed by the moderate group, and the lowest in the mild group, while Oxygenation Index (OI) was the lowest in the severe group, followed by the moderate group, and the highest in the mild group (p < 0.05). Multivariate logistic regression analysis found that the disease grade (severe), TLR7 mRNA expression, IL-23 level, and IL-17 level were the risk factors affecting the 28-d survival status of ARDS patients (OR > 1, p < 0.05). CONCLUSIONS: In ARDS patients, the TLR7/IL-23/IL-17 signaling pathway is activated. The expression of this pathway is closely related to the severity of the disease and the levels of lung injury markers, and it is a risk factor that may have a direct impact on the prognosis of ARDS patients.
Assuntos
Interleucina-17 , Interleucina-23 , Síndrome do Desconforto Respiratório , Transdução de Sinais , Receptor 7 Toll-Like , Humanos , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/genética , Interleucina-17/sangue , Feminino , Masculino , Receptor 7 Toll-Like/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Interleucina-23/sangue , Adulto , Idoso , Prognóstico , Estudos de Casos e Controles , Índice de Gravidade de Doença , RNA Mensageiro/análise , Fatores de Risco , Leucócitos Mononucleares/metabolismo , Relevância ClínicaRESUMO
Skin psoriasis is defined as receiving external stimulation to activate skin dendritic cells (DCs) which can release interleukin 23 (IL-23) to interlink the innate and adaptive immunity as well as induce T helper 17 (Th17) cell differentiation leading to elevated production of interleukin 17 (IL-17) for keratinocytes over production. This autoimmune loop in psoriasis pathogenesis is influenced by G protein-coupled receptor (GPCR) signalling transduction, and in particular, function of adhesion molecule GPR97 in psoriasis endures to be utterly addressed. In this research, our team allocated GPR97 depletion (GPR97-/-), GPR97 conditional depletion on dendritic cell (DC-cKO), and keratin 14-conditional knockout (K14-cKO) mice models to explore the function of GPR97 which influences keratinocytes and skin immunity. It was found that significantly aggravated psoriasis-like lesion in GPR97-/- mice. In addition, hyperproliferative keratinocytes as well as accumulation of DCs and Th17 cells were detected in imiquimod (IMQ)-induced GPR97-/- mice, which was consistent with the results in DC-cKO and K14-cKO psoriasis model. Additional investigations indicated that beclomethasone dipropionate (BDP), an agonist of GPR97, attenuated the psoriasis-like skin disease and restricted HaCaT cells abnormal proliferation as well as Th17 cells differentiation. Particularly, we found that level of NF-κB p65 was increased in GPR97-/- DCs and BDP could inhibit p65 activation in DCs. Role of GPR97 is indispensable and this adhesion receptor may affect immune cell enrichment and function in skin and alter keratinocytes proliferation as well as differentiation in psoriasis.
Assuntos
Imiquimode , Interleucina-17 , Interleucina-23 , Queratinócitos , Camundongos Knockout , Psoríase , Receptores Acoplados a Proteínas G , Transdução de Sinais , Células Th17 , Animais , Psoríase/induzido quimicamente , Psoríase/patologia , Psoríase/genética , Psoríase/metabolismo , Interleucina-17/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/deficiência , Camundongos , Queratinócitos/metabolismo , Queratinócitos/patologia , Células Th17/imunologia , Células Th17/metabolismo , Interleucina-23/metabolismo , Células Dendríticas/metabolismo , Camundongos Endogâmicos C57BL , Humanos , Modelos Animais de Doenças , Pele/patologia , Pele/metabolismoRESUMO
Candida albicans Is a leading cause of nosocomial bloodstream infections, particularly in immunocompromised patients. Current therapeutic strategies are insufficient, highlighting the need for effective vaccines. This study aimed to evaluate the efficacy of a dual-antigen fusion protein vaccine (AH) targeting the Als3 and Hyr1 proteins of C. albicans, using AlPO4 as an adjuvant. The AH vaccine was constructed by fusing Als317-432 and Hyr125-350 proteins, and its immunogenicity was tested in BALB/c mice and New Zealand white rabbits. Mice received three intramuscular doses of the vaccine combined with AlPO4, followed by a lethal challenge with C. albicans SC5314. Survival rates, antibody responses, cytokine production, fungal burdens, and organ pathology were assessed. The vaccine's efficacy was also validated using rabbit serum. Mice vaccinated with the AH-AlPO4 combination exhibited significantly higher antibody titers, particularly IgG and its subclasses, compared to controls (p < .001). The survival rate of vaccinated mice was 80% post-infection, significantly higher than the control group (p < .01). Vaccinated mice showed reduced fungal loads in the blood, kidneys, spleen, and liver (p < .05). Increased levels of interferon gamma and interleukin (IL)-17A were observed, indicating robust T helper (Th) 1 and Th17 cell responses. Vaccination mitigated organ damage, with kidney and liver pathology scores significantly lower than those of unvaccinated mice (p < .05). Rabbit serum with polyclonal antibodies demonstrated effective antifungal activity, confirming vaccine efficacy across species. The AH-AlPO4 vaccine effectively induced strong immune responses, reduced fungal burden, and protected against organ pathology in C. albicans infections. These findings support further development of dual-antigen vaccine strategies.
Candida, a fungus, is a major cause of bloodstream infections, especially in critical care settings. This study focused on developing a vaccine to protect against Candida infection. The vaccine targeted two key proteins, Als3p and Hyr1p, found on the surface of Candida, using a combination of these proteins. To create the vaccine, we used Als3p and Hyr1p to form a fusion protein called AH, and tested the vaccine on mice, administering it with different adjuvants (substances that enhance the immune response). The results showed that the AH vaccine, particularly when combined with the adjuvant AlPO4, induced a strong immune response in mice. This response included the production of specific antibodies and immune cells that are crucial for defending against Candida infections. Furthermore, mice receiving the AH-AlPO4 vaccine showed significantly better survival rates and lower levels of fungal infection compared to the control group or another experimental group. The vaccine also protected vital organs, such as the kidneys and liver, from Candida-induced damage. Additionally, we used rabbit serum to validate the efficacy of the vaccine, providing cross-species confirmation of its effectiveness. The study demonstrated the potential of the AH vaccine in eliciting robust immune responses and reducing the severity of Candida albicans infections. In summary, this research introduces a promising AH vaccine, which shows effectiveness in protecting against Candida infections. The study's innovative approach and positive results contribute to the ongoing efforts to develop vaccines against fungal infections, addressing a critical healthcare challenge. Further research is needed to explore the vaccine's long-term effectiveness and safety for potential use in clinical settings.
Assuntos
Adjuvantes Imunológicos , Anticorpos Antifúngicos , Antígenos de Fungos , Candida albicans , Candidíase , Vacinas Fúngicas , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão , Animais , Vacinas Fúngicas/imunologia , Vacinas Fúngicas/administração & dosagem , Candida albicans/imunologia , Candidíase/prevenção & controle , Candidíase/imunologia , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Coelhos , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/genética , Camundongos , Feminino , Antígenos de Fungos/imunologia , Antígenos de Fungos/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Proteínas Fúngicas/imunologia , Proteínas Fúngicas/administração & dosagem , Citocinas , Vacinação/métodos , Imunoglobulina G/sangue , Modelos Animais de Doenças , Interleucina-17/imunologia , Interferon gama/imunologia , Eficácia de Vacinas , Análise de Sobrevida , Compostos de AlúmenRESUMO
Renovascular hypertension (RH), a secondary hypertension, can significantly impact heart health, resulting in heart damage and dysfunction, thereby elevating the risk of cardiovascular diseases. Coniferol (CA), which has vascular relaxation properties, is expected to be able to treat hypertension-related diseases. However, its potential effects on cardiac function after RH remain unclear. In this study, in combination with network pharmacology, the antihypertensive and cardioprotective effects of CA in a two-kidney, one-clip (2K1C) mice model and its ability to mitigate angiotensin II (Ang II)-induced hypertrophy in H9C2 cells were investigated. The findings revealed that CA effectively reduced blood pressure, myocardial tissue damage, and inflammation after RH. The possible targets of CA for RH treatment were screened by network pharmacology. The interleukin-17 (IL-17) and tumor necrosis factor (TNF) signaling pathways were identified using a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The inflammatory response was identified using a Gene Ontology (GO) enrichment analysis. Western blot analysis confirmed that CA reduced the expression of IL-17, matrix metallopeptidase 9 (MMP9), cyclooxygenase 2 (COX2), and TNF α in heart tissues and the H9C2 cells. In summary, CA inhibited cardiac inflammation and fibrohypertrophy following RH. This effect was closely linked to the expression of MMP9/COX2/TNF α/IL-17. This study sheds light on the therapeutic potential of CA for treating RH-induced myocardial hypertrophy and provides insights into its underlying mechanisms, positioning CA as a promising candidate for future drug development.
Assuntos
Hipertensão Renovascular , Farmacologia em Rede , Animais , Hipertensão Renovascular/tratamento farmacológico , Hipertensão Renovascular/metabolismo , Hipertensão Renovascular/patologia , Camundongos , Masculino , Modelos Animais de Doenças , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Fator de Necrose Tumoral alfa/metabolismo , Ratos , Interleucina-17/metabolismo , Angiotensina II/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Diferenciação Celular , Interleucina-23 , Queratinócitos , Malassezia , Células Th17 , Malassezia/imunologia , Queratinócitos/microbiologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Células Th17/imunologia , Animais , Interleucina-23/metabolismo , Humanos , Camundongos , Transdução de Sinais , NF-kappa B/metabolismo , Receptor 2 Toll-Like/metabolismo , Interleucina-17/metabolismo , Pele/microbiologia , Pele/patologia , Pele/imunologia , Modelos Animais de Doenças , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Células Cultivadas , Camundongos Endogâmicos C57BL , Interleucina 22RESUMO
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.
Assuntos
Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Sinvastatina , Linfócitos T Reguladores , Células Th17 , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Células Th17/imunologia , Células Th17/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Sinvastatina/farmacologia , Sinvastatina/administração & dosagem , Camundongos , Feminino , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Interleucina-17/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Medula Espinal/imunologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Humanos , Fator de Crescimento Transformador beta/metabolismo , Modelos Animais de DoençasRESUMO
BACKGROUND: Thyroid-associated ophthalmopathy (TAO) is an autoimmune condition commonly linked with Graves' disease (GD), characterized by orbital tissue inflammation and fibrosis. It is hypothesized that gene polymorphisms may influence production of the IL-17 and IL-38 cytokines, thereby impacting TAO development and progression. This study focused on investigating the gene polymorphisms of IL-17 (rs9463772 C/T in IL17F) and IL-38 (rs3811058 C/T, rs7570267 A/G in IL1F10) in patients with GD. METHODS: A case-control study was conducted on 132 patients with TAO and 153 patients without TAO according to eligibility criteria. After clinical examination blood samples were collected for further investigations. Genotyping was performed with the TaqMan™ Master Mix kit. Allele and genotype frequencies were compared between studied groups and subgroups. RESULTS: No significant differences were found in age, duration of GD, or thyroid hormone between patients with and without TAO. However, a higher predisposition to develop TAO was observed among smokers (OR = 1.682, p = 0.03). Overall, no significant associations between gene polymorphisms and TAO development were identified in GD patients. Further analysis revealed that the CC genotype in IL1F10 rs3811058 polymorphism among Caucasians was associated with an increased risk of TAO (OR = 2.7, p = 0.02), as well as allele differences were also significant (OR = 2.8, p = 0.001). CONCLUSIONS: These findings shed light on TAO genetic predispositions in Kazakhstani GD patients, notably among Caucasians, underscoring the need for further research. These results may offer valuable targets for the development of novel treatments for TAO.
Assuntos
Predisposição Genética para Doença , Genótipo , Oftalmopatia de Graves , Interleucina-17 , Interleucinas , Polimorfismo de Nucleotídeo Único , Humanos , Oftalmopatia de Graves/genética , Oftalmopatia de Graves/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Estudos de Casos e Controles , Interleucina-17/genética , Interleucinas/genética , Frequência do Gene , DNA/genética , AlelosRESUMO
In response to pro-inflammatory cytokines such as interleukin (IL)-1ß, dental pulp fibroblasts produce various inflammatory mediators, including IL-6, IL-8, CC chemokine ligand 20 (CCL20), and CXC chemokine ligand 10 (CXCL10), leading to the progression of pulpitis. IL-17/IL-17A (IL-17A) is a pro-inflammatory cytokine secreted by T helper (Th) 17 cells following their recruitment to inflamed sites; however, the roles of IL-17A during pulpitis remain unclear. The purpose of this study was to investigate the effect of IL-17A on IL-6, IL-8, CCL20 and CXCL10 production by human dental pulp fibroblasts (HDPFs) in vitro. IL-17A at a concentration of 100 ng/ml induced the production of 10 times more IL-8 and 4 times more CXCL10, but not IL-6 and CCL20, compared to controls. Co-stimulation of HDPFs with IL-17A and IL-1ß synergistically enhanced the production of IL-6, CCL20, IL-8 and CXCL10. IL-1ß increased expression of IL-17 receptor/IL-17RA (IL-17R) on HDPFs. Moreover, the cell signal pathways of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were more potently activated by simultaneous stimulation with IL-17A and IL-1ß. These findings suggest that IL-17A participates in the progression of dental pulp inflammation through the enhanced production of inflammatory mediators in HDPFs.
Assuntos
Quimiocina CXCL10 , Polpa Dentária , Fibroblastos , Interleucina-17 , Interleucina-1beta , Interleucina-6 , Interleucina-8 , Humanos , Polpa Dentária/citologia , Polpa Dentária/metabolismo , Polpa Dentária/efeitos dos fármacos , Interleucina-17/farmacologia , Interleucina-17/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Interleucina-1beta/metabolismo , Quimiocina CXCL10/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Mediadores da Inflamação/metabolismo , Quimiocina CCL20/metabolismo , Pulpite/metabolismo , Células Cultivadas , NF-kappa B/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Receptores de Interleucina-17/metabolismoRESUMO
The human colonic commensal enterotoxigenic Bacteroides fragilis (ETBF) is associated with chronic colitis and colon cancer. ETBF colonization induces colitis via the Bacteroides fragilis toxin (BFT). BFT secreted by ETBF cause colon inflammation via E-cadherin cleavage/NF-κB signaling. ETBF promotes colon tumorigenesis via interleukin 17A (IL-17A)/CXCL-dependent inflammation, but its bioactive therapeutics in ETBF-promoted tumorigenesis remain unexplored. In the current study, we investigated the caffeic acid phenethyl ester (CAPE) in the murine model of ETBF colitis and tumorigenesis. In this study, we observed that CAPE treatment mitigated inflammation induced by ETBF in mice. Additionally, our findings indicate that CAPE treatment offers protective effects against ETBF-enhanced colon tumorigenesis in a mouse model of colitis-associated colon cancer induced by azoxymethane (AOM) and dextran sulfate sodium. Notably, the decrease in colon tumorigenesis following CAPE administration correlates with a reduction in the expression of IL-17A and CXCL1 in the gastrointestinal tract. The molecular mechanism for CAPE-induced protection against ETBF-mediated tumorigenesis is mediated by IL-17A/CXCL1, and by NF-κB activity in intestinal epithelial cells. Our findings indicate that CAPE may serve as a preventive agent against the development of ETBF-induced colitis and colorectal cancer (CRC).
Assuntos
Bacteroides fragilis , Ácidos Cafeicos , Colite , Álcool Feniletílico , Animais , Ácidos Cafeicos/farmacologia , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Bacteroides fragilis/efeitos dos fármacos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/microbiologia , Camundongos Endogâmicos C57BL , Interleucina-17/metabolismo , Camundongos , Carcinogênese/efeitos dos fármacos , Quimiocina CXCL1/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/prevenção & controle , Neoplasias do Colo/patologia , Neoplasias do Colo/microbiologia , Masculino , Colo/efeitos dos fármacos , Colo/patologia , Colo/microbiologia , Colo/metabolismo , Toxinas Bacterianas/toxicidade , Modelos Animais de Doenças , Azoximetano/toxicidade , Sulfato de Dextrana , Metaloendopeptidases/metabolismoRESUMO
Pregnancy is associated with profound changes in immunity. However, pregnancy-related respiratory immune adaptations in response to influenza infection and their impact on disease severity remain unclear. Here, we describe, in a preclinical model of mid-gestation pregnancy, a mechanism of enhanced host defense against influenza A virus (IAV) localized to the nasal cavity that limits viral replication and reduces the magnitude of intrapulmonary immune responses. Consequently, the pregnant mice show reduced pulmonary pathology and preserved airway function after IAV infection. The early restriction of viral replication is independent of type I interferon (IFN) but dependent on increased antimicrobial peptides (AMPs) driven by interleukin-17+ (IL-17+) γδ+ T cells within the nasal passages. This pathway of host defense against IAV infection in the upper airways during pregnancy restricts early viral infection and prevents virus dissemination into the lung supporting maternal fitness.
Assuntos
Vírus da Influenza A , Interferon Tipo I , Interleucina-17 , Mucosa Nasal , Infecções por Orthomyxoviridae , Animais , Feminino , Gravidez , Interleucina-17/metabolismo , Interleucina-17/imunologia , Camundongos , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Mucosa Nasal/imunologia , Mucosa Nasal/virologia , Mucosa Nasal/metabolismo , Vírus da Influenza A/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Replicação Viral , Pulmão/imunologia , Pulmão/virologiaRESUMO
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.
Assuntos
Interleucina-17 , Queloide , Células Th17 , Humanos , Interleucina-17/metabolismo , Interleucina-17/imunologia , Queloide/tratamento farmacológico , Queloide/imunologia , Queloide/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Pele/patologia , Pele/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismoRESUMO
INTRODUCTION: Porokeratosis (PK) is an autoinflammatory keratinization disease (AIKD) characterized by circular or annular skin lesions with a hyperkeratotic rim, pathologically shown as the cornoid lamella. Four genes that cause PK are associated with the mevalonate (MV) pathway. In Chinese PK patients, mevalonate diphosphate decarboxylase (MVD) is the most common causative gene. The lack of an animal model has greatly limited research on PK pathogenesis. MATERIALS AND METHODS: In this research, we constructed K14-CreERT2-Mvdfl/fl mice using the Cre-LoxP system to create a mouse model for in-depth studies of PK. The Epidermal Mvd gene was knocked out by intraperitoneal injection of Tamoxifen (TAM). Pathology, immunohistochemistry, RNA-seq, and Western Blot analysis were performed. RESULTS: Skin lesions appeared following Mvd deficiency, and pathological examination revealed the characteristic cornoid lamella, as well as cutaneous inflammation. Furthermore, we observed elevated levels of IL-17A and IL-1ß, and a decreased Loricrin level in epidermal Mvd-deficient mice. Compared with the wild-type (WT) group, Mvd deficiency activated the expression of lipid metabolism-related proteins. CONCLUSION: We developed the first mouse model for PK research, enabling further studies on disease development and treatment approaches.