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2.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34544860

RESUMO

Frozen shoulder is a common fibroproliferative disease characterized by the insidious onset of pain and restricted range of shoulder movement with a significant socioeconomic impact. The pathophysiological mechanisms responsible for chronic inflammation and matrix remodeling in this prevalent fibrotic disorder remain unclear; however, increasing evidence implicates dysregulated immunobiology. IL-17A is a key cytokine associated with inflammation and tissue remodeling in numerous musculoskeletal diseases, and thus, we sought to determine the role of IL-17A in the immunopathogenesis of frozen shoulder. We demonstrate an immune cell landscape that switches from a predominantly macrophage population in nondiseased tissue to a T cell-rich environment in disease. Furthermore, we observed a subpopulation of IL-17A-producing T cells capable of inducing profibrotic and inflammatory responses in diseased fibroblasts through enhanced expression of the signaling receptor IL-17RA, rendering diseased cells more sensitive to IL-17A. We further established that the effects of IL-17A on diseased fibroblasts was TRAF-6/NF-κB dependent and could be inhibited by treatment with an IKKß inhibitor or anti-IL-17A antibody. Accordingly, targeting of the IL-17A pathway may provide future therapeutic approaches to the management of this common, debilitating disease.


Assuntos
Bursite/fisiopatologia , Fibrose/patologia , Inflamação/patologia , Interleucina-17/imunologia , Linfócitos T/imunologia , Estudos de Casos e Controles , Células Cultivadas , Citocinas/metabolismo , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/imunologia , Fibrose/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Transdução de Sinais
3.
Biomed Pharmacother ; 142: 111980, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34364043

RESUMO

One of the hallmarks of COVID-19 is the cytokine storm that provokes primarily pneumonia followed by systemic inflammation. Emerging evidence has identified a potential link between elevated interleukin-17A (IL-17A) levels and disease severity and progression. Considering that per se, IL-17A can activate several inflammatory pathways, it is plausible to hypothesize an involvement of this cytokine in COVID-19 clinical outcomes. Thus, IL-17A could represent a marker of disease progression and/or a target to develop therapeutic strategies. This hypothesis paper aims to propose this "unique" cytokine as a silent amplifier of the COVID-19 immune response and (potentially) related therapy.


Assuntos
COVID-19 , Síndrome da Liberação de Citocina , Interleucina-17 , Biomarcadores/sangue , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/imunologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Progressão da Doença , Descoberta de Drogas , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-17/sangue , Interleucina-17/imunologia , Índice de Gravidade de Doença
4.
Biomed Res Int ; 2021: 8112783, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34447853

RESUMO

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.


Assuntos
Vírus da Influenza A/patogenicidade , MicroRNAs/genética , Infecções por Orthomyxoviridae/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Vírus da Influenza A/isolamento & purificação , Interleucina-17/genética , Interleucina-17/imunologia , MicroRNAs/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , RNA Longo não Codificante/imunologia , RNA Mensageiro/imunologia , Ratos , Ratos Sprague-Dawley
5.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360808

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.


Assuntos
Esclerose Amiotrófica Lateral/imunologia , Células-Tronco Pluripotentes Induzidas/imunologia , Interleucina-17/imunologia , Neurônios Motores/imunologia , Proteína FUS de Ligação a RNA/imunologia , Células Th17/imunologia , Esclerose Amiotrófica Lateral/patologia , Sobrevivência Celular/imunologia , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Neurônios Motores/patologia , Células Th17/patologia
6.
Nat Commun ; 12(1): 5024, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408137

RESUMO

There is an unmet clinical need for stratification of breast lesions as indolent or aggressive to tailor treatment. Here, single-cell transcriptomics and multiparametric imaging applied to a mouse model of breast cancer reveals that the aggressive tumor niche is characterized by an expanded basal-like population, specialization of tumor subpopulations, and mixed-lineage tumor cells potentially serving as a transition state between luminal and basal phenotypes. Despite vast tumor cell-intrinsic differences, aggressive and indolent tumor cells are functionally indistinguishable once isolated from their local niche, suggesting a role for non-tumor collaborators in determining aggressiveness. Aggressive lesions harbor fewer total but more suppressed-like T cells, and elevated tumor-promoting neutrophils and IL-17 signaling, disruption of which increase tumor latency and reduce the number of aggressive lesions. Our study provides insight into tumor-immune features distinguishing indolent from aggressive lesions, identifies heterogeneous populations comprising these lesions, and supports a role for IL-17 signaling in aggressive progression.


Assuntos
Neoplasias da Mama/imunologia , Mama/patologia , Evasão Tumoral , Animais , Mama/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Neutrófilos/imunologia , Análise de Célula Única
7.
Nat Microbiol ; 6(9): 1110-1117, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34341528

RESUMO

The role of the microbiota in the development and function of γδ T cells-a T cell subset characterized by a T cell receptor composed of one γ-chain and one δ-chain-has been investigated in multiple organs in mice and humans. Interactions between the microbiota and γδ T cells affect both tissue homeostasis and disease pathologies. Notably, microbiota-induced interleukin-17 (IL-17)-producing-γδ T cells can mediate a range of immunological processes, from metabolic disorders to neuroinflammation via the gut-brain axis. However, the bidirectional interactions between γδ T cells and the microbiota have not been fully determined. In this Perspective, we dissect the roles of microbiota in modulating γδ T cell development and function, and evaluate the evidence for γδ T cell selection of commensal communities. We also discuss the potential implications of these cells in health and disease and the major open questions and research avenues in the field.


Assuntos
Microbioma Gastrointestinal , Subpopulações de Linfócitos T/imunologia , Animais , Encéfalo/imunologia , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Neuroimunomodulação , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia
8.
Front Immunol ; 12: 653611, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290697

RESUMO

Ankylosing spondylitis (AS) is a chronic autoimmune inflammatory disease that mainly affects the axial and sacroiliac joints. Single-nucleotide polymorphisms (SNPs) in genes encoding cytokines have been associated with AS, which can interfere with the production of these cytokines and contribute to the development of AS. In order to contribute to a better understanding of the pathology of AS, our objective was to investigate a possible association of the IL10 -1082 A>G SNP (rs1800896) with AS and to evaluate the serum levels of TNF-α, IL-10, IL-17A, and IL-17F in AS patients and controls comparing them with their respective genotypes (TNF rs1800629, IL10 rs1800896, IL17A rs2275913, and IL17F rs763780). Patients and controls were selected from the Maringá University Hospital and the Maringá Rheumatism Clinic, in Paraná State, Southern Brazil, and they were diagnosed by the ASAS Criteria. In total, 149 patients and 169 controls were genotyped for the IL10 -1082 A>G polymorphism using a polymerase chain reaction with sequence specific primers (PCR-SSP); the measurement of TNF-α serum levels was performed through the immunofluorimetric test and IL-10, IL-17A, and IL-17F using an ELISA test. There was a high frequency of the IL10 -1082 G allele in AS patients compared with controls with an odds ratio of 1.83 and 95% confidence interval of 1.32 to 2.54, and a significant difference in the genotype frequencies of the IL10 -1082 A/G+G/G between patients and healthy controls, with an odds ratio of 3.01 and 95% confidence interval of 1.75 to 5.17. In addition, increased serum levels of IL-10 were observed in AS patients: 2.38 (IQR, 0.91) pg/ml compared with controls 1.72 (IQR 0.93) pg/ml (P = 0.01). Our results also showed an association between IL17F rs763780 C/T+T/T genotypes and increased serum levels of IL-17F in patients with AS and also in controls. We can conclude that patients with the A/G and G/G genotypes for -1082 A>G (rs1800896) in the IL10 gene are three times more likely to develop AS, that the serum level of IL-10 was higher in AS patients and that the IL17F rs763780 polymorphism can affect the levels of IL-17F in the serum of patients and controls in the same way.


Assuntos
Predisposição Genética para Doença , Interleucina-10/genética , Espondilite Anquilosante/genética , Adulto , Alelos , Brasil , Estudos de Casos e Controles , Feminino , Frequência do Gene , Humanos , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-17/sangue , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/sangue , Espondilite Anquilosante/imunologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
9.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299314

RESUMO

Signal transducer and activator of transcription 1 (STAT1) acts as a tumor suppressor molecule in colitis-associated colorectal cancer (CAC), particularly during the very early stages, modulating immune responses and controlling mechanisms such as apoptosis and cell proliferation. Previously, using an experimental model of CAC, we reported increased intestinal cell proliferation and faster tumor development, which were consistent with more signs of disease and damage, and reduced survival in STAT1-/- mice, compared with WT counterparts. However, the mechanisms through which STAT1 might prevent colorectal cancer progression preceded by chronic inflammation are still unclear. Here, we demonstrate that increased tumorigenicity related to STAT1 deficiency could be suppressed by IL-17 neutralization. The blockade of IL-17 in STAT1-/- mice reduced the accumulation of CD11b+Ly6ClowLy6G+ cells resembling granulocytic myeloid-derived suppressor cells (MDSCs) in both spleen and circulation. Additionally, IL-17 blockade reduced the recruitment of neutrophils into intestinal tissue, the expression and production of inflammatory cytokines, and the expression of intestinal STAT3. In addition, the anti-IL-17 treatment also reduced the expression of Arginase-1 and inducible nitric oxide synthase (iNOS) in the colon, both associated with the main suppressive activity of MDSCs. Thus, a lack of STAT1 signaling induces a significant change in the colonic microenvironment that supports inflammation and tumor formation. Anti-IL-17 treatment throughout the initial stages of CAC related to STAT1 deficiency abrogates the tumor formation possibly caused by myeloid cells.


Assuntos
Neoplasias Associadas a Colite/etiologia , Granulócitos/patologia , Interleucina-17/fisiologia , Fator de Transcrição STAT1/fisiologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Neoplasias Associadas a Colite/patologia , Neoplasias Associadas a Colite/fisiopatologia , Progressão da Doença , Feminino , Granulócitos/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/fisiopatologia , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Microambiente Tumoral/imunologia
10.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201664

RESUMO

The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal through IL-17R. Five subunits of IL-17R have been described to date, which couple to form a homo- or hetero-receptor complex. Characteristically, IL-17RA is a common subunit in all hetero-receptors. IL-17RA has unique structural-containing a SEFIR/TILL domain-and functional-requiring ACT-1 for signaling-properties, enabling Th17 cells to act as a bridge between innate and adaptive immune cells. In psoriasis, IL-17RA plays a key role in pathogenesis based on: (a) IL-17A, IL-17F, and other IL-17 isoforms are involved in disease development; and (b) IL-17RA is essential for signaling of all IL-17 cytokines but IL-17D, whose receptor has not been identified to date. This article reviews current evidence on the biology and role of the IL-17 family of cytokines and receptors, with focus on IL-17RA, in psoriasis and some related comorbidities, and puts them in context with current and upcoming treatments.


Assuntos
Psoríase/tratamento farmacológico , Psoríase/etiologia , Receptores de Interleucina-17/fisiologia , Anticorpos Monoclonais Humanizados/farmacologia , Humanos , Interleucina-17/imunologia , Interleucina-17/metabolismo , Isoformas de Proteínas
11.
Cytokine ; 146: 155627, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34237556

RESUMO

BACKGROUND: One of the main pathophysiological mechanisms underlying the severe course of COVID-19 is the hyper-inflammatory syndrome associated with progressive damage of lung tissue and multi-organ dysfunction. IL-17 has been suggested to be involved in hyper-inflammatory syndrome. OBJECTIVE: To evaluate the efficacy and safety of the IL-17 inhibitor netakimab in patients with severe COVID-19. STUDY DESIGN: In our retrospective case-control study we evaluated the efficacy of netakimab in hospitalized patients with severe COVID-19 outside the intensive care unit (ICU). Patients in the experimental group were treated with standard of care therapy and netakimab at a dose of 120 mg subcutaneously. RESULTS: 171 patients with severe COVID-19 were enrolled in our study, and 88 of them received netakimab. On the 3 day of therapy, body temperature, SpO2/FiO2, NEWS2 score, and CRP improved significantly in the netakimab group compared to the control group. Other clinical outcomes such as transfer to ICU (11.4% vs 9.6%), need for mechanical ventilation (10.2% vs 9.6%), 28-day mortality (10.2% vs 8.4%), did not differ between the groups. CONCLUSION: In hospitalized patients with severe COVID-19, anti-IL-17 therapy might mitigate the inflammatory response and improve oxygenation, but do not affect the need for mechanical ventilation and mortality.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/terapia , Hospitalização/estatística & dados numéricos , Pacientes Internados/estatística & dados numéricos , Interleucina-17/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , COVID-19/complicações , COVID-19/virologia , Estudos de Casos e Controles , Diarreia/induzido quimicamente , Dispneia/induzido quimicamente , Feminino , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Interleucina-17/imunologia , Interleucina-17/metabolismo , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Respiração Artificial , Estudos Retrospectivos , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Resultado do Tratamento
12.
Front Immunol ; 12: 618581, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267743

RESUMO

Spondyloarthritis (SpA) is a spectrum of chronic inflammatory joint diseases that frequently presents with inflammation of the axial skeleton, peripheral joints, entheses, skin, and gut. Understanding SpA pathogenesis has been proven challenging due to the limited availability of human target tissues. In recent years, the interleukin (IL)-23/IL-17 pathway has been implicated in the pathogenesis of SpA, in addition to the Tumor Necrosis Factor Alpha (TNF-α) cytokine. The underlying molecular mechanisms by which the IL-23/IL-17 pathway triggers disease initiation, both in the joints as well as at extra-musculoskeletal sites, are not precisely known. Animal models that resemble pathological features of human SpA have provided possibilities for in-depth molecular analyses of target tissues during various phases of the disease, including the pre-clinical initiation phase of the disease before arthritis and spondylitis are clinically present. Herein, we summarize recent insights gained in SpA animal models on the role of the IL-23/IL-17 pathway in immune activation across affected sites in SpA, which include the joint, entheses, gut and skin. We discuss how local activation of the IL-23/IL-17 axis may contribute to the development of tissue inflammation and the onset of clinically manifest SpA. The overall aim is to provide the reader with an overview of how the IL-23/IL-17 axis could contribute to the onset of SpA pathogenesis. We discuss how insights from animal studies into the initiation phase of disease could instruct validation studies in at-risk individuals and thereby provide a perspective for potential future preventive treatment.


Assuntos
Modelos Animais de Doenças , Interleucina-17/imunologia , Interleucina-23/imunologia , Espondilartrite/imunologia , Animais , Humanos , Inflamação , Interleucina-17/genética , Interleucina-23/genética , Camundongos , Ratos , Espondilartrite/etiologia
13.
Front Immunol ; 12: 626895, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267744

RESUMO

In mammals, Interleukin-17 cytokine family plays critical roles in both acute and chronic inflammatory responses. In fish species, three Interleukin-17A/F (IL-17A/F) genes have been identified to be homologous to mammalian IL-17A and IL-17F, but little is known about their functional activity. In this study, Pf_IL-17A/F1, 2 and 3 genes were cloned from yellow catfish (Pelteobagrus fulvidraco) and they differed in protein structure and exon length, implying that they may have divergent bioactivity. Real-time quantitative PCR analyses revealed that three Pf_IL-17A/F genes were highly expressed in blood and mucosal tissues (skin+mucus and gill) from healthy adult fish. The mRNA expressions of Pf_IL-17A/F1, 2 and 3 genes were significantly up-regulated in the gill, skin+mucus, head kidney and spleen after challenge with Edwardsiella ictaluri and in the isolated peripheral blood leucocytes (PBLs) of yellow catfish after stimulation with phytohaemagglutinin (PHA), lipopolysaccharides (LPS), peptidoglycan (PGN) and polyinosinic-polycytidylic acid (Poly I:C). These results indicate that Pf_IL-17A/F1, 2 and 3 genes may play a vital role in the regulation of immune against pathogens. Additionally, the recombinant (r) Pf_IL-17A/F1, 2 and 3 proteins significantly induced the mRNA expressions of proinflammatory cytokines, chemokines and antibacterial peptides genes, and the rPf_IL-17A/F 2 and 3 proteins promoted phagocytosis of PBLs more powerfully than the rPf_IL-17A/F1. Furthermore, the rPf_IL-17A/F1, 2 and 3 proteins might activate the NF-κB and MAPK signal pathways by IL-17RA, ACT1, TRAF6, TRAF2, TRAF5 and TAK1, indicating that the three Pf_IL-17A/F proteins may play different roles in promoting inflammatory response.


Assuntos
Peixes-Gato/genética , Peixes-Gato/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Animais , Rim Cefálico/imunologia , Interleucina-17/química , Interleucina-17/classificação , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Lipopolissacarídeos/farmacologia , Peptidoglicano/farmacologia , Fito-Hemaglutininas/farmacologia , Poli I-C/farmacologia , Baço/imunologia
14.
Molecules ; 26(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071080

RESUMO

The main purpose of this study was to investigate whether the blockade of the interaction between the receptor activator of nuclear factor-κB (NF-ĸB) ligand (RANKL) and its receptor RANK as well as the blockade of NF-κB inhibitor kinase (IKK) and of NF-κB translocation have the potential to suppress the pathogenesis of allergic asthma by inhibition and/or enhancement of the production by CD4+ and CD8+ T cells of important cytokines promoting (i.e., IL-4 and IL-17) and/or inhibiting (i.e., IL-10 and TGF-ß), respectively, the development of allergic asthma. Studies using ovalbumin(OVA)-immunized mice have demonstrated that all the tested therapeutic strategies prevented the OVA-induced increase in the absolute number of IL-4- and IL-17-producing CD4+ T cells (i.e., Th2 and Th17 cells, respectively) indirectly, i.e., through the inhibition of the clonal expansion of these cells in the mediastinal lymph nodes. Additionally, the blockade of NF-κB translocation and RANKL/RANK interaction, but not IKK, prevented the OVA-induced increase in the percentage of IL-4-, IL-10- and IL-17-producing CD4+ T cells. These latter results strongly suggest that both therapeutic strategies can directly decrease IL-4 and IL-17 production by Th2 and Th17 cells, respectively. This action may constitute an important mechanism underlying the anti-asthmatic effect induced by the blockade of NF-κB translocation and of RANKL/RANK interaction. Thus, in this context, both these therapeutic strategies seem to have an advantage over the blockade of IKK. None of the tested therapeutic strategies increased both the absolute number and frequency of IL-10- and TGF-ß-producing Treg cells, and hence they lacked the potential to inhibit the development of the disease via this mechanism.


Assuntos
Asma/imunologia , Asma/metabolismo , Animais , Asma/fisiopatologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Hipersensibilidade/fisiopatologia , Imunoglobulina E/imunologia , Interleucina-17/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos
15.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071562

RESUMO

The skin is the outermost layer of the body and is exposed to many environmental stimuli, which cause various inflammatory immune responses in the skin. Among them, fungi are common microorganisms that colonize the skin and cause cutaneous fungal diseases such as candidiasis and dermatophytosis. The skin exerts inflammatory responses to eliminate these fungi through the cooperation of skin-component immune cells. IL-17 producing cells are representative immune cells that play a vital role in anti-fungal action in the skin by producing antimicrobial peptides and facilitating neutrophil infiltration. However, the actual impact of IL-17-producing cells in cutaneous fungal infections remains unclear. In this review, we focused on the role of IL-17-producing cells in a series of cutaneous fungal infections, the characteristics of skin infectious fungi, and the recognition of cell components that drive cutaneous immune cells.


Assuntos
Candidíase/imunologia , Fungos/imunologia , Interleucina-17/imunologia , Pele/imunologia , Células Th17/imunologia , Tinha/imunologia , Animais , Candidíase/microbiologia , Fungos/fisiologia , Humanos , Interleucina-17/metabolismo , Infiltração de Neutrófilos/imunologia , Proteínas Citotóxicas Formadoras de Poros/imunologia , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Pele/microbiologia , Células Th17/metabolismo , Tinha/microbiologia
16.
Gene ; 793: 145750, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34077777

RESUMO

OBJECTIVE: Graves' disease (GD) is a common autoimmune disease manifesting with diffuse symmetric thyroid gland enlargement, pretibial myxedema, and Graves' ophthalmopathy (GO). Recently, the vitamin D receptor (VDR) gene has been linked to various autoimmune diseases. This study aimed to investigate the association of VDR gene polymorphisms with susceptibility to GD and GO in the Southwest Chinese Han population. METHODS: A two-stage association study was performed in 1,209 controls and 650 GD patients by PCR-RFLP assay. Real-time PCR and ELISA were carried out to quantify gene expression and cytokine production. RESULTS: The first-stage study showed that the frequency of VDR/Apa I AA genotype was significantly increased in GD (Pc = 1.67 × 10-2, OR = 1.98). The second-stage and combined studies confirmed the association of VDR/Apa I with GD (AA genotype: Pc = 3.45 × 10-4, OR = 1.87; A allele: Pc = 2.62 × 10-2, OR = 1.20). The stratification analysis showed that GO patients had a higher frequency of the VDR/Apa I AA genotype (Pc = 8.69 × 10-5, OR = 2.84). Functional experiments showed a decreased VDR expression and TGF-ß1 production as well as an increased IL-17 production in VDR/Apa I AA genotype carriers. CONCLUSION: The VDR/Apa I polymorphism is significantly associated with GD and GO, and it may be involved in the development of GD and GO by influencing VDR mRNA expression levels and the secretion levels of cytokines.


Assuntos
Predisposição Genética para Doença , Oftalmopatia de Graves/genética , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Desoxirribonucleases de Sítio Específico do Tipo II/química , Feminino , Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Oftalmopatia de Graves/etnologia , Oftalmopatia de Graves/imunologia , Oftalmopatia de Graves/patologia , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Receptores de Calcitriol/imunologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia
17.
Front Immunol ; 12: 649591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995368

RESUMO

Psoriasis is a chronic proliferative autoimmune dermatologic disease characterised by abnormal angiogenesis. Thus, regulating angiogenesis in the skin is an important treatment strategy for psoriasis. PSORI-CM02, an empirical Chinese medicine formula optimised from Yin Xie Ling, was created by the Chinese medicine specialist, Guo-Wei Xuan. Clinical studies have shown that PSORI-CM02 is safe and effective for the treatment of psoriasis. However, its anti-psoriatic mechanisms remain to be further explored. In this study, we investigated the effects of PSORI-CM02 on angiogenesis in the skin and the underlying mechanisms in IL-17A-stimulated human umbilical vein endothelial cells (HUVECs) and a murine model of imiquimod (IMQ)-induced psoriasis. In vitro, PSORI-CM02 significantly inhibited the proliferation and migration of IL-17A-stimulated HUVECs in a dose-dependent manner. Further, it markedly regulated the antioxidative/oxidative status and inflammation; suppressed the expression of VEGF, VEGFR1, VEGFR2, ANG1, and HIF-1α; and reduced the phosphorylation of MAPK signalling pathway components in IL-17A-stimulated HUVECs. In vivo studies showed that PSORI-CM02 markedly reduced angiogenesis in the skin of mice with IMQ-induced psoriasis, while significantly rebalancing antioxidant/oxidant levels; inhibiting the production of IL-6, TNF-α, IL-17A, and IL-17F; and repressing the synthesis of angiogenic mediators. In addition, PSORI-CM02 markedly reduced the activation of the MAPK signalling pathway in psoriatic skin tissue. Taken together, our results demonstrated that PSORI-CM02 inhibited psoriatic angiogenesis by reducing the oxidative status and inflammation, suppressing the expression of angiogenesis-related molecules, and inhibiting the activation of the MAPK signalling pathway in vitro and in vivo.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Neovascularização Patológica/tratamento farmacológico , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Células Endoteliais da Veia Umbilical Humana , Humanos , Imiquimode/administração & dosagem , Imiquimode/toxicidade , Interleucina-17/imunologia , Interleucina-17/metabolismo , Queratinócitos , Masculino , Camundongos , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Pele/irrigação sanguínea , Pele/imunologia , Pele/patologia
18.
Front Immunol ; 12: 645143, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33959126

RESUMO

The reason why only few coeliac patients develop the cutaneous manifestation of the disease, named dermatitis herpetiformis (DH), is still unknown. Epidermal transglutaminase (TG3) has been described as the main autoantigen of humoral immunity in DH but the mechanisms leading to this autoimmune response remain obscure. Here we characterized T cells from skin, gut and peripheral blood of DH and coeliac disease (CD) patients, evaluated the impact of the gluten-free diet on circulating T lymphocytes' phenotype and investigated antigen specific T cell response toward epidermal and tissue transglutaminase (TG2). DH patients showed an increased frequency of skin-derived T cells producing TNFα when compared to CD patients. Moreover, circulating T cells producing TNFα and IL-17A positively correlated with clinical score of skin disease activity and decreased after gluten-free diet. Finally, TG2 and TG3-specific T cells resulted more reactive to antigens stimulation in DH patients and showed cross reactivity toward the two autoantigens in both the group of patients. Our data suggest a role of TNFα and IL-17A producing cells in the development of DH and, for the first time, show the existence of a crossed T cell response toward the two transglutaminases isoforms, thus suggesting new insights on T cells role in skin damage.


Assuntos
Doença Celíaca/imunologia , Dermatite Herpetiforme/imunologia , Proteínas de Ligação ao GTP/imunologia , Linfócitos T/imunologia , Transglutaminases/imunologia , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Interleucina-17/imunologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/imunologia
19.
J Immunol ; 206(10): 2386-2392, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33952619

RESUMO

Periodontal disease (PD) is a chronic destructive inflammatory disease of the tooth-supporting structures that leads to tooth loss at its advanced stages. Although the disease is initiated by a complex organization of oral microorganisms in the form of a plaque biofilm, it is the uncontrolled immune response to periodontal pathogens that fuels periodontal tissue destruction. IL-17A has been identified as a key cytokine in the pathogenesis of PD. Despite its well documented role in host defense against invading pathogens at oral barrier sites, IL-17A-mediated signaling can also lead to a detrimental inflammatory response, causing periodontal bone destruction. In this study, we developed a local sustained delivery system that restrains IL-17A hyperactivity in periodontal tissues by incorporating neutralizing anti-IL-17A Abs in poly(lactic-coglycolic) acid microparticles (MP). This formulation allowed for controlled release of anti-IL-17A in the periodontium of mice with ligature-induced PD. Local delivery of anti-IL-17A MP after murine PD induction inhibited alveolar bone loss and osteoclastic activity. The anti-IL-17A MP formulation also decreased expression of IL-6, an IL-17A target gene known to induce bone resorption in periodontal tissues. This study demonstrates proof of concept that local and sustained release of IL-17A Abs constitutes a promising therapeutic strategy for PD and may be applicable to other osteolytic bone diseases mediated by IL-17A-driven inflammation.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/imunologia , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Sistemas de Liberação de Medicamentos/métodos , Interleucina-17/imunologia , Periodontite/tratamento farmacológico , Periodontite/imunologia , Animais , Cápsulas , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Osteólise/tratamento farmacológico , Osteólise/imunologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Resultado do Tratamento
20.
Front Immunol ; 12: 662362, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981308

RESUMO

Psoriasis is a recurrent autoimmune skin disease with aberrant regulation of keratinocytes and immunocytes. There is no universally accepted single treatment available for psoriasis, and the establishment of a common treatment option to control its signs and symptoms is urgently needed. Here, we found Ebosin, a novel exopolysaccharide isolated from Streptomyces sp. 139 by our lab, not only could ameliorate inflammation in LPS-induced keratinocytes through IKK/NF-kapaB pathway, but also attenuate psoriatic skin lesions and reduce inflammatory factors expression in imiquimod (IMQ)-mediated psoriatic mice. Except for inhibiting the expression of epidermal differentiation related proteins, Ebosin significantly increased the percentage of CD4+Foxp3+CD25+ Tregs and decreased CD4+IL17A+ Th17 cells in psoriatic mice. Furthermore, we demonstrate that Ebosin significantly suppressed the IL-17 signaling pathway via A20 (encoded by tnfaip3) in vivo. As the direct binding of tnfaip3 to miR-155 has been demonstrated by luciferase reporter assay, and Ebosin has been demonstrated to inhibit miR-155 level in vitro and in vivo, our study first indicates that Ebosin reduces inflammation through the miR-155-tnfaip3-IL-17 axis and T cell differentiation in a psoriasis-like model. Thus, we conclude that Ebosin can act as a promising therapeutic candidate for the treatment of psoriasis.


Assuntos
Inflamação/prevenção & controle , Interleucina-17/metabolismo , MicroRNAs/metabolismo , Polissacarídeos Bacterianos/administração & dosagem , Psoríase/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Células HaCaT , Humanos , Inflamação/tratamento farmacológico , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/imunologia , Polissacarídeos Bacterianos/imunologia , Psoríase/tratamento farmacológico , Psoríase/imunologia , Transdução de Sinais/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/imunologia
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