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1.
Elife ; 132024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38722677

RESUMO

Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA (Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the Mirlet7b/Mirlet7c2 cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the Mirlet7b/Mirlet7c2 cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing Mirlet7g in T cells are resistant to Tc17 and CD4+IL17a+ T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (RORγt), as a direct target of Mirlet7 in T cells. Overall, our findings shed light on the Mirlet7/RORγt axis with Mirlet7 acting as a molecular brake in the generation of Tc17 cells and suggest a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.


Assuntos
Diferenciação Celular , Regulação para Baixo , MicroRNAs , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Humanos , Células Th17/imunologia , Células Th17/metabolismo , Enfisema Pulmonar/genética , Enfisema Pulmonar/metabolismo , Enfisema Pulmonar/patologia , Enfisema/genética , Enfisema/metabolismo , Camundongos Endogâmicos C57BL , Pulmão/patologia , Pulmão/metabolismo , Masculino , Interleucina-17/metabolismo , Interleucina-17/genética , Feminino
2.
Front Immunol ; 15: 1378040, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38698866

RESUMO

Background: Interleukin-17-producing CD4 T cells contribute to the control of Mycobacterium tuberculosis (Mtb) infection in humans; whether infection with human immunodeficiency virus (HIV) disproportionately affects distinct Th17-cell subsets that respond to Mtb is incompletely defined. Methods: We performed high-definition characterization of circulating Mtb-specific Th17 cells by spectral flow cytometry in people with latent TB and treated HIV (HIV-ART). We also measured kynurenine pathway activity by liquid chromatography-mass spectrometry (LC/MS) on plasma and tested the hypothesis that tryptophan catabolism influences Th17-cell frequencies in this context. Results: We identified two subsets of Th17 cells: subset 1 defined as CD4+Vα7.2-CD161+CD26+and subset 2 defined as CD4+Vα7.2-CCR6+CXCR3-cells of which subset 1 was significantly reduced in latent tuberculosis infection (LTBI) with HIV-ART, yet Mtb-responsive IL-17-producing CD4 T cells were preserved; we found that IL-17-producing CD4 T cells dominate the response to Mtb antigen but not cytomegalovirus (CMV) antigen or staphylococcal enterotoxin B (SEB), and tryptophan catabolism negatively correlates with both subset 1 and subset 2 Th17-cell frequencies. Conclusions: We found differential effects of ART-suppressed HIV on distinct subsets of Th17 cells, that IL-17-producing CD4 T cells dominate responses to Mtb but not CMV antigen or SEB, and that kynurenine pathway activity is associated with decreases of circulating Th17 cells that may contribute to tuberculosis immunity.


Assuntos
Antígenos de Bactérias , Infecções por HIV , Interleucina-17 , Tuberculose Latente , Mycobacterium tuberculosis , Células Th17 , Humanos , Mycobacterium tuberculosis/imunologia , Células Th17/imunologia , Células Th17/metabolismo , Interleucina-17/metabolismo , Interleucina-17/imunologia , Antígenos de Bactérias/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Triptofano/metabolismo , Cinurenina/metabolismo , Imunofenotipagem , Fenótipo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
3.
Int J Mol Sci ; 25(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38731877

RESUMO

Epstein-Barr virus (EBV) DNA is known to be shed upon reactivation of latent EBV. Based on our previous findings linking Toll-like receptor-9 (TLR9) to an EBV DNA-driven surge in IL-17A production, we aimed to examine the therapeutic potential of TLR9 inhibition in EBV DNA-exacerbated arthritis in a collagen-induced arthritis (CIA) mouse model. C57BL/6J mice were administered either collagen, EBV DNA + collagen, EBV DNA + collagen + TLR9 inhibitor, or only the TLR9 inhibitor. After 70 days, paw thicknesses, clinical scores, and gripping strength were recorded. Moreover, affected joints, footpads, and colons were histologically scored. Furthermore, the number of cells co-expressing IL-17A, IFN-γ, and FOXP3 in joint sections was determined by immunofluorescence assays. Significantly decreased paw thicknesses, clinical scores, and histological scores with a significantly increased gripping strength were observed in the group receiving EBV DNA + collagen + TLR9 inhibitor, compared to those receiving EBV DNA + collagen. Similarly, this group showed decreased IL-17A+ IFN-γ+, IL-17A+ FOXP3+, and IL-17A+ IFN-γ+ FOXP3+ foci counts in joints. We show that inhibiting TLR9 limits the exacerbation of arthritis induced by EBV DNA in a CIA mouse model, suggesting that TLR9 could be a potential therapeutic target for rheumatoid arthritis management in EBV-infected individuals.


Assuntos
Artrite Experimental , DNA Viral , Modelos Animais de Doenças , Herpesvirus Humano 4 , Camundongos Endogâmicos C57BL , Receptor Toll-Like 9 , Animais , Receptor Toll-Like 9/metabolismo , Camundongos , Herpesvirus Humano 4/fisiologia , Artrite Experimental/virologia , Artrite Experimental/patologia , Artrite Experimental/metabolismo , DNA Viral/genética , Interleucina-17/metabolismo , Masculino , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/virologia
4.
Arch Dermatol Res ; 316(5): 176, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38758283

RESUMO

Psoriasis is a chronic immune mediated inflammatory skin disease with systemic manifestations. It has been reported that caloric restriction could improve severity of psoriasis patients. However, the mechanism of intermittent fasting effects on psoriasis has not been investigated. Caloric restriction is known to reduce the number of circulating inflammatory monocytes in a CCL2-dependent manner. However, it is still unknown whether caloric restriction can improve psoriasis by regulating monocytes through CCL2. In this study, we used imiquimod (IMQ)-induced psoriasis-like mouse model to explore the effects and the mechanisms of intermittent fasting on psoriasis-like dermatitis. We found that intermittent fasting could significantly improve IMQ-induced psoriasis-like dermatitis, and reduce the number of γδT17 cells and IL-17 production in draining lymph nodes and psoriatic lesion via inhibiting proliferation and increasing death of γδT17 cells. Furthermore, intermittent fasting could significantly decrease monocytes in blood, and this was associated with decreased monocytes, macrophages and DC in psoriasis-like skin inflammation. Reduced monocytes in circulation and increased monocytes in BM of fasting IMQ-induced psoriasis-like mice is through reducing the production of CCL2 from BM to inhibit monocyte egress to the periphery. Our above data shads light on the mechanisms of intermittent fasting on psoriasis.


Assuntos
Quimiocina CCL2 , Modelos Animais de Doenças , Jejum , Imiquimode , Monócitos , Psoríase , Animais , Psoríase/imunologia , Psoríase/induzido quimicamente , Psoríase/patologia , Monócitos/imunologia , Monócitos/metabolismo , Camundongos , Jejum/sangue , Quimiocina CCL2/metabolismo , Células Th17/imunologia , Interleucina-17/metabolismo , Pele/patologia , Pele/imunologia , Humanos , Camundongos Endogâmicos C57BL , Masculino , Proliferação de Células , Restrição Calórica , Jejum Intermitente
5.
Fish Shellfish Immunol ; 149: 109612, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38705548

RESUMO

SH2 domain containing inositol polyphosphate5-phosphatase-2 (SHIP2) is a member of the 5-phosphatase family, acting as a vital negative regulator of immune response in vertebrates. In the present study, a SHIP2 homologue (designed as CgSHIP2) was identified from Pacific oyster, Crassostrea gigas. There was a SH2 domain, an IPPc domain and a SAM domain in CgSHIP2. The mRNA transcripts of CgSHIP2 were widely expressed in all the tested tissues with the highest expression in haemolymph. The mRNA expressions of CgSHIP2 in haemocytes increased significantly at 6, 12, 48 and 72 h after Vibrio splendidus stimulation. The positive green signals of CgSHIP2 protein were mainly located in cytoplasm of haemocytes. After the expression of CgSHIP2 was inhibited by RNA interference, the mRNA transcripts of interleukin 17s (CgIL-17-1, CgIL-17-2, CgIL-17-3 and CgIL-17-6) in the haemocytes increased significantly at 24 h after V. splendidus stimulation, which were 8.15-fold (p < 0.001), 3.44-fold (p < 0.05), 2.15-fold (p < 0.01) and 4.63-fold (p < 0.05) compared with that in NC-RNAi group, respectively. Obvious branchial swelling and cilium shedding in gills were observed in CgSHIP2-RNAi group at 24 h after V. splendidus stimulation. The results suggested that CgSHIP2 played an important role in controlling inflammatory response induced by bacteria in oysters.


Assuntos
Crassostrea , Regulação da Expressão Gênica , RNA Mensageiro , Vibrio , Animais , Crassostrea/imunologia , Crassostrea/genética , Vibrio/fisiologia , Regulação da Expressão Gênica/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Imunidade Inata/genética , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Filogenia , Sequência de Aminoácidos , Perfilação da Expressão Gênica/veterinária , Alinhamento de Sequência/veterinária , Hemócitos/imunologia
6.
J Immunol Res ; 2024: 5582151, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38690552

RESUMO

Unlike T cells in other tissues, uterine T cells must balance strong immune defense against pathogens with tolerance to semiallogeneic fetus. Our previous study fully elucidated the characteristics of γδT cells in nonpregnant uterus and the mechanism modulated by estrogen. However, comprehensive knowledge of the immunological properties of αßT (including CD4+T cells and CD8+T) cells in nonpregnancy uterus has not been acquired. In this study, we fully compared the immunological properties of αßT cells between uterus and blood using mouse and human sample. It showed that most of CD4+T cells and CD8+T cells in murine uterus and human endometrium were tissue resident memory T cells which highly expressed tissue residence markers CD69 and/or CD103. In addition, both CD4+T cells and CD8+T cells in uterus highly expressed inhibitory molecular PD-1 and cytokine IFN-γ. Uterine CD4+T cells highly expressed IL-17 and modulated by transcription factor pSTAT3. Moreover, we compared the similarities and differences between human and murine uterine T cell phenotype. Together, uterine CD4+T cells and CD8+ cells exhibited a unique mixed signature of T cell dysfunction, activation, and effector function which enabled them to balance strong immune defense against pathogens with tolerance to fetus. Our study fully elucidated the unique immunologic properties of uterine CD4+T and CD8+T cells and provided a base for further investigation of functions.


Assuntos
Antígenos CD , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Útero , Feminino , Linfócitos T CD8-Positivos/imunologia , Animais , Humanos , Camundongos , Linfócitos T CD4-Positivos/imunologia , Útero/imunologia , Antígenos CD/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/genética , Cadeias alfa de Integrinas/metabolismo , Células T de Memória/imunologia , Fator de Transcrição STAT3/metabolismo , Interferon gama/metabolismo , Lectinas Tipo C/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Interleucina-17/metabolismo , Ativação Linfocitária/imunologia , Memória Imunológica
7.
Sci Rep ; 14(1): 10340, 2024 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710764

RESUMO

This study aims to evaluate the role of trefoil factor 3 (TFF3) peptides in type 2 diabetes mellitus (T2DM) from an inflammatory perspective. The focus was on exploring how TFF3 affects the function of T cells. TFF3 overexpression model was constructed using lentivirus in Jurkat cell lines. We evaluated the impact of TFF3 on the proliferation, apoptosis, and IL-17A levels of Jurkat cells cultured in high glucose. The T2DM model was induced in TFF3 knockout (KO) mice through streptozotocin combined with high-fat diet. The measurements included glucose tolerance, insulin tolerance, inflammation markers, Th17 cell proportion, and pancreatic pathological changes. The T2DM modeling led to splenomegaly in mice, and increased expression of TFF3 in their spleens. Overexpression of TFF3 increased the proportion of IL-17+ T cells and the levels of Th17-related cytokines in Jurkat cells. There was no difference in body weight and blood glucose levels between wild-type and TFF3 KO mice. However, T2DM mice lacking the TFF3 gene showed improved glucose utilization, ameliorated pancreatic pathology, decreased inflammation levels, and reduced Th17 cell ratio. TFF3 may be involved in the chronic inflammatory immune response in T2DM. Its mechanism may be related to the regulation of the RORγt/IL-17 signaling pathway and its impact on T cell proliferation and apoptosis.


Assuntos
Diabetes Mellitus Tipo 2 , Camundongos Knockout , Células Th17 , Fator Trefoil-3 , Células Th17/imunologia , Células Th17/metabolismo , Animais , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Camundongos , Fator Trefoil-3/metabolismo , Fator Trefoil-3/genética , Células Jurkat , Interleucina-17/metabolismo , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Masculino , Proliferação de Células , Apoptose , Dieta Hiperlipídica/efeitos adversos
8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 40(4): 373-377, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-38710521

RESUMO

Patients with Hashimoto's thyroiditis had increased numbers of Th17 cells in serum and thyroid tissue, significantly elevated levels of interleukin 17 (IL-17), and an imbalance in the ratio of Th17 cells to regulatory T cells (Tregs). The reduced Tregs' ratio leads to a reduction in immunosuppressive function within the thyroid gland, while Th17 cells are involved in the development of HT by regulating the expression of pro-inflammatory cytokines in the thyroid gland and mediating thyroid tissue fibrosis through the secretion of IL-17.


Assuntos
Doença de Hashimoto , Interleucina-17 , Linfócitos T Reguladores , Células Th17 , Doença de Hashimoto/imunologia , Doença de Hashimoto/sangue , Doença de Hashimoto/metabolismo , Humanos , Interleucina-17/metabolismo , Interleucina-17/sangue , Células Th17/imunologia , Células Th17/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Animais
9.
Nat Commun ; 15(1): 3756, 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38704381

RESUMO

The human pathogen Neisseria gonorrhoeae ascends into the upper female reproductive tract to cause damaging inflammation within the Fallopian tubes and pelvic inflammatory disease (PID), increasing the risk of infertility and ectopic pregnancy. The loss of ciliated cells from the epithelium is thought to be both a consequence of inflammation and a cause of adverse sequelae. However, the links between infection, inflammation, and ciliated cell extrusion remain unresolved. With the use of ex vivo cultures of human Fallopian tube paired with RNA sequencing we defined the tissue response to gonococcal challenge, identifying cytokine, chemokine, cell adhesion, and apoptosis related transcripts not previously recognized as potentiators of gonococcal PID. Unexpectedly, IL-17C was one of the most highly induced genes. Yet, this cytokine has no previous association with gonococcal infection nor pelvic inflammatory disease and thus it was selected for further characterization. We show that human Fallopian tubes express the IL-17C receptor on the epithelial surface and that treatment with purified IL-17C induces pro-inflammatory cytokine secretion in addition to sloughing of the epithelium and generalized tissue damage. These results demonstrate a previously unrecognized but critical role of IL-17C in the damaging inflammation induced by gonococci in a human explant model of PID.


Assuntos
Tubas Uterinas , Gonorreia , Inflamação , Interleucina-17 , Neisseria gonorrhoeae , Humanos , Feminino , Tubas Uterinas/microbiologia , Tubas Uterinas/patologia , Tubas Uterinas/imunologia , Neisseria gonorrhoeae/imunologia , Neisseria gonorrhoeae/patogenicidade , Interleucina-17/metabolismo , Gonorreia/imunologia , Gonorreia/microbiologia , Gonorreia/patologia , Inflamação/patologia , Inflamação/microbiologia , Doença Inflamatória Pélvica/microbiologia , Doença Inflamatória Pélvica/patologia , Doença Inflamatória Pélvica/imunologia , Citocinas/metabolismo , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-17/genética , Adulto , Epitélio/patologia , Epitélio/microbiologia
10.
BMC Oral Health ; 24(1): 530, 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38704553

RESUMO

OBJECTIVE: Explore the therapeutic mechanism of Coptidis Rhizome (CR) in periodontitis using network pharmacology, and validate it through molecular docking and in vitro experiments. METHODS: Screened potential active components and target genes of CR from TCMSP and Swiss databases. Identified periodontitis-related target genes using GeneCards. Found common target genes using Venny. Conducted GO and KEGG pathway analysis. Performed molecular docking and in vitro experiments using Berberine, the main active component of CR, on lymphocytes from healthy and periodontitis patients. Assessed effects on inflammatory factors using CCK-8, flow cytometry, and ELISA. RESULTS: Fourteen active components and 291 targets of CR were identified. 30 intersecting target genes with periodontitis were found. GO and KEGG analysis revealed oxidative stress response and IL-17 signaling pathway as key mechanisms. Molecular docking showed strong binding of Berberine with ALOX5, AKT1, NOS2, and TNF. In vitro experiments have demonstrated the ability of berberine to inhibit the expression of Th17 + and other immune related cells in LPS stimulated lymphocytes, and reduce the secretion of IL-6, IL-8, and IL-17. CONCLUSION: CR treats periodontitis through a multi-component, multi-target, and multi-pathway approach. Berberine, its key component, acts through the IL-17 signaling pathway to exert anti-inflammatory effects.


Assuntos
Berberina , Medicamentos de Ervas Chinesas , Simulação de Acoplamento Molecular , Farmacologia em Rede , Periodontite , Humanos , Periodontite/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Berberina/farmacologia , Berberina/uso terapêutico , Coptis chinensis , Rizoma , Interleucina-17/metabolismo , Transdução de Sinais/efeitos dos fármacos , Técnicas In Vitro , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo
11.
PeerJ ; 12: e17268, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38708351

RESUMO

Objective: To study the efficacy of PADTM Plus-based photoactivated disinfection (PAD) for treating denture stomatitis (DS) in diabetic rats by establishing a diabetic rat DS model. Methods: The diabetic rat DS model was developed by randomly selecting 2-month-old male Sprague-Dawley rats and dividing them into four groups. The palate and denture surfaces of rats in the PAD groups were incubated with 1 mg/mL toluidine blue O for 1 min each, followed by a 1-min exposure to 750-mW light-emitting diode light. The PAD-1 group received one radiation treatment, and the PAD-2 group received three radiation treatments over 5 days with a 1-day interval. The nystatin (NYS) group received treatment for 5 days with a suspension of NYS of 100,000 IU. The infection group did not receive any treatment. In each group, assessments included an inflammation score of the palate, tests for fungal load, histological evaluation, and immunohistochemical detection of interleukin-17 (IL-17) and tumor necrosis factor (TNF-α) conducted 1 and 7 days following the conclusion of treatment. Results: One day after treatment, the fungal load on the palate and dentures, as well as the mean optical density values of IL-17 and TNF-α, were found to be greater in the infection group than in the other three treatment groups (P < 0.05). On the 7th day after treatment, these values were significantly higher in the infection group than in the PAD-2 and NYS groups (P < 0.05). Importantly, there were no differences between the infection and PAD-1 groups nor between the PAD-2 and NYS groups (P > 0.05). Conclusions: PAD effectively reduced the fungal load and the expressions of IL-17 and TNF-α in the palate and denture of diabetic DS rats. The efficacy of multiple-light treatments was superior to that of single-light treatments and similar to that of NYS.


Assuntos
Diabetes Mellitus Experimental , Desinfecção , Ratos Sprague-Dawley , Estomatite sob Prótese , Animais , Masculino , Ratos , Estomatite sob Prótese/microbiologia , Estomatite sob Prótese/radioterapia , Estomatite sob Prótese/tratamento farmacológico , Desinfecção/métodos , Cloreto de Tolônio/farmacologia , Cloreto de Tolônio/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-17/metabolismo , Modelos Animais de Doenças
12.
PeerJ ; 12: e17374, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38756445

RESUMO

Background: An increased level of interleukin-17A and interleukin-18 in the serum and intestinal mucosa of celiac disease patients reflecting the severity of villous atrophy and inflammation was documented. Thus, the objective of this study was to evaluate the concentrations of salivary-17A, interleukin-1 beta, and interleukin-18 in patients with celiac disease who are on a gluten-free diet, both with and without periodontitis, and to compare these levels with those in healthy individuals. Methods: The study involved 23 participants with serologically confirmed celiac disease (CD) and 23 control subjects. The CD patients had been following a gluten-free diet (GFD) for a minimum of 1 year and had no other autoimmune disorders. The research involved collecting demographic data, conducting periodontal examinations, gathering unstimulated whole saliva, and performing enzyme-linked immunosorbent assays to measure salivary interleukin-17A, interleukin-1 beta, and interleukin-18 levels. Spearman's correlation analysis was utilized to explore the relationships between CD markers in patients on a GFD and their periodontal clinical findings. Results: The periodontal findings indicated significantly lower values in celiac disease patients adhering to a gluten-free diet compared to control subjects (p = 0.001). No significant differences were found in salivary IL-17A, IL-18, and IL-1B levels between celiac disease patients and control subjects. Nevertheless, the levels of all interleukins were elevated in periodontitis patients in both the celiac and control groups. The IL-1 Beta level was significantly higher in periodontitis patients compared to non-periodontitis patients in the control group (p = 0.035). Significant negative correlations were observed between serum IgA levels and plaque index (r = -0.460, p = 0.010), as well as gingival index (r = -0.396, p = 0.030) in CD patients on a gluten-free diet. Conclusion: Celiac disease patients on gluten-free diet exhibited better periodontal health compared to control subjects. However, increased levels of salivary IL-17A, IL-18 and IL-1B levels were associated with periodontitis. Additionally, serum IgA level was significantly inversely associated with periodontitis clinical manifestations and with salivary inflammatory mediators in CD patients on GFD.


Assuntos
Doença Celíaca , Dieta Livre de Glúten , Interleucina-17 , Interleucina-18 , Periodontite , Saliva , Humanos , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Doença Celíaca/sangue , Doença Celíaca/diagnóstico , Interleucina-17/sangue , Interleucina-17/metabolismo , Interleucina-17/análise , Masculino , Feminino , Interleucina-18/sangue , Interleucina-18/análise , Interleucina-18/metabolismo , Saliva/química , Saliva/imunologia , Adulto , Periodontite/imunologia , Periodontite/metabolismo , Periodontite/sangue , Interleucina-1beta/sangue , Interleucina-1beta/análise , Interleucina-1beta/metabolismo , Estudos de Casos e Controles , Pessoa de Meia-Idade , Biomarcadores/sangue , Biomarcadores/análise , Adulto Jovem
13.
Front Immunol ; 15: 1375654, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38698841

RESUMO

Background: Inflammatory bowel disease (IBD) is often associated with complex extraintestinal manifestations. The incidence of nonalcoholic fatty liver disease (NAFLD) in IBD populations is increasing yearly. However, the mechanism of interaction between NAFLD and IBD is not clear. Consequently, this study aimed to explore the common genetic characteristics of IBD and NAFLD and identify potential therapeutic targets. Materials and methods: Gene chip datasets for IBD and NAFLD were obtained from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to identify modules in those datasets related to IBD and NAFLD. ClueGO was used for biological analysis of the shared genes between IBD and NAFLD. Based on the Human MicroRNA Disease Database (HMDD), microRNAs (miRNAs) common to NAFLD and IBD were obtained. Potential target genes for the miRNAs were predicted using the miRTarbase, miRDB, and TargetScan databases. Two-sample Mendelian randomization (MR) and two-way MR were used to explore the causal relationship between Interleukin-17 (IL-17) and the risk of IBD and NAFLD using data from GWAS retrieved from an open database. Results: Through WGCNA, gene modules of interest were identified. GO enrichment analysis using ClueGO suggested that the abnormal secretion of chemokines may be a common pathophysiological feature of IBD and NAFLD, and that the IL-17-related pathway may be a common key pathway for the pathological changes that occur in IBD and NAFLD. The core differentially expressed genes (DEGs) in IBD and NAFLD were identified and included COL1A1, LUM, CCL22, CCL2, THBS2, COL1A2, MMP9, and CXCL8. Another cohort was used for validation. Finally, analysis of the miRNAs identified potential therapeutic targets. The MR results suggested that although there was no causal relationship between IBD and NAFLD, there were causal relationships between IL-17 and IBD and NAFLD. Conclusion: We established a comorbid model to explain the potential mechanism of IBD with NAFLD and identified the chemokine-related pathway mediated by cytokine IL-17 as the core pathway in IBD with NAFLD, in which miRNA also plays a role and thus provides potential therapeutic targets.


Assuntos
Doenças Inflamatórias Intestinais , Análise da Randomização Mendeliana , Hepatopatia Gordurosa não Alcoólica , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Redes Reguladoras de Genes , MicroRNAs/genética , Interleucina-17/genética , Interleucina-17/metabolismo , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Perfilação da Expressão Gênica , Polimorfismo de Nucleotídeo Único
14.
Oncol Res ; 32(4): 625-641, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38560562

RESUMO

The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer (NSCLC). Although researchers have disclosed that interleukin 17 (IL-17) can increase matrix metalloproteinases (MMPs) induction causing NSCLC cell metastasis, the underlying mechanism remains unclear. In the study, we found that IL-17 receptor A (IL-17RA), p300, p-STAT3, Ack-STAT3, and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17. p300, STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3, Ack-STAT3 and MMP19 level as well as the cell migration and invasion. Mechanism investigation revealed that STAT3 and p300 bound to the same region (-544 to -389 nt) of MMP19 promoter, and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity, p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17. Meanwhile, p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact, synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion. Besides, the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300, STAT3 or MMP19 gene plus IL-17 treatment, the nodule number, and MMP19, Ack-STAT3, or p-STAT3 production in the lung metastatic nodules were all alleviated. Collectively, these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation, which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Camundongos , Animais , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Interleucina-17/genética , Interleucina-17/metabolismo , Fosforilação , Neoplasias Pulmonares/patologia , Acetilação , Camundongos Nus , Transcrição Gênica , Movimento Celular/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica
15.
J Transl Med ; 22(1): 328, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38566145

RESUMO

BACKGROUND: Psoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism. METHODS: We conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated. RESULTS: DNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5-/- DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions. CONCLUSIONS: DNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.


Assuntos
Interleucina-17 , Psoríase , Humanos , Camundongos , Animais , Interleucina-17/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Psoríase/terapia , Pele/patologia , Imiquimode/efeitos adversos , Imiquimode/metabolismo , Inflamação/patologia , Linfócitos T/metabolismo , Modelos Animais de Doenças
16.
J Ethnopharmacol ; 328: 118131, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38565408

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sarcandra glabra is officially named Zhong Jie Feng as a traditional medicine. In the nationality of Yao and Zhuang, it has been used to treat digestive diseases like stomachache and dysentery. Similarly, in Dai nationality, it has been used to treat intestinal diseases like gastric ulcers. However, the effect and mechanism of S. glabra on experimental ulcerative colitis (UC) are known. AIM OF STUDY: The main objective of this study was to investigate the effect and mechanism of S. glabra on experimental UC. MATERIALS AND METHODS: The chemical components in the water extract of S. glabra (ZJF) were analyzed by UPLC-MS/MS method. The HCoEpiC cell line was used to assess the promotive effect on intestinal proliferation and restitution. RAW264.7 cells were used to assess the in vitro anti-inflammatory effect of ZJF. The 3% DSS-induced colitis model was used to evaluate the in vivo effect of ZJF (4.5 g/kg and 9.0 g/kg). Mesalazine (0.5 g/kg) was used as the positive drug. ELISA, RT-qPCR, Western blot, and multiplex immunohistochemical experiments were used to test gene levels in the colon tissue. The H&E staining method was used to monitor the pathological changes of colon tissue. TUNEL assay kit was used to detect apoptosis of epithelial colonic cells. RESULTS: ZJF could alleviate the DSS-caused colitis in colon tissues, showing a comparative effect to that of the positive drug mesalazine. Mechanism study indicated that ZJF could promote normal colonic HCoEpiC cell proliferation and restitution, inhibit overexpression of pro-inflammatory cytokines, restore the M1/M2 ratio, decrease epithelial colonic cell apoptosis, rescue tight junction protein levels, and modulate IL-17/Notch1/FoxP3 pathway to treat experimental UC. CONCLUSION: Our results indicated that S. glabra can promote intestinal cell restitution, balance immune response, and modulate IL-17/Notch1/FoxP3 pathway to treat experimental UC.


Assuntos
Colite Ulcerativa , Colite , Animais , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Mesalamina/efeitos adversos , Cromatografia Líquida , Interleucina-17/metabolismo , Espectrometria de Massas em Tandem , Colo , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Fatores de Transcrição/metabolismo , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
17.
Artigo em Chinês | MEDLINE | ID: mdl-38604686

RESUMO

OBJECTIVE: To investigate the effect of LAG-3 deficiency (LAG3-/-) on natural killer (NK) cell function and hepatic fibrosis in mice infected with Echinococcus multilocularis. METHODS: C57BL/6 mice, each weighing (20 ± 2) g, were divided into the LAG3-/- and wild type (WT) groups, and each mouse in both groups was inoculated with 3 000 E. multilocularis protoscoleces via the hepatic portal vein. Mouse liver and spleen specimens were collected 12 weeks post-infection, sectioned and stained with sirius red, and the hepatic lesions and fibrosis were observed. Mouse hepatic and splenic lymphocytes were isolated, and flow cytometry was performed to detect the proportions of hepatic and splenic NK cells, the expression of CD44, CD25 and CD69 molecules on NK cell surface, and the secretion of interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin (IL)-4, IL-10 and IL-17A. RESULTS: Sirius red staining showed widening of inflammatory cell bands and hyperplasia of fibrotic connective tissues around mouse hepatic lesions, as well as increased deposition of collagen fibers in the LAG3-/-group relative to the WT group. Flow cytometry revealed lower proportions of mouse hepatic (6.29% ± 1.06% vs. 11.91% ± 1.85%, P < 0.000 1) and splenic NK cells (4.44% ± 1.22% vs. 5.85% ± 1.10%, P > 0.05) in the LAG3-/- group than in the WT group, and the mean fluorescence intensity of CD44 was higher on the surface of mouse hepatic NK cells in the LAG3-/- group than in the WT group (t = -3.234, P < 0.01), while no significant differences were found in the mean fluorescence intensity of CD25 or CD69 on the surface of mouse hepaticNK cells between the LAG3-/- and WT groups (both P values > 0.05). There were significant differences between the LAG3-/- and WT groups in terms of the percentages of IFN-γ (t = -0.723, P > 0.05), TNF-α (t = -0.659, P > 0.05), IL-4 (t = -0.263, P > 0.05), IL-10 (t = -0.455, P > 0.05) or IL-17A secreted by mouse hepatic NK cells (t = 0.091, P > 0.05), and the percentage of IFN-γ secreted by mouse splenic NK cells was higher in the LAG3-/- group than in the WT group (58.40% ± 1.64% vs. 50.40% ± 4.13%; t = -4.042, P < 0.01); however, there were no significant differences between the two groups in terms of the proportions of TNF-α (t = -1.902, P > 0.05), IL-4 (t = -1.333, P > 0.05), IL-10 (t = -1.356, P > 0.05) or IL-17A secreted by mouse splenic NK cells (t = 0.529, P > 0.05). CONCLUSIONS: During the course of E. multilocularis infections, LAG3-/- promotes high-level secretion of IFN-γ by splenic NK cells, which may participate in the reversal the immune function of NK cells, resulting in aggravation of hepatic fibrosis.


Assuntos
Echinococcus multilocularis , Interleucina-10 , Animais , Camundongos , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-17/farmacologia , Interleucina-4/metabolismo , Interleucina-4/farmacologia , Echinococcus multilocularis/genética , Fator de Necrose Tumoral alfa/metabolismo , Camundongos Endogâmicos C57BL , Interferon gama/genética , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Cirrose Hepática/genética
18.
Biochem Biophys Res Commun ; 710: 149832, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38588614

RESUMO

BACKGROUND: Sepsis-induced acute lung injury (ALI) is associated with considerable morbidity and mortality in critically ill patients. S100A9, a key endothelial injury factor, is markedly upregulated in sepsis-induced ALI; however, its specific mechanism of action has not been fully elucidated. METHODS: The Gene Expression Omnibus database transcriptome data for sepsis-induced ALI were used to screen for key differentially expressed genes (DEGs). Using bioinformatics analysis methods such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction network analyses, the pathogenesis of sepsis-induced ALI was revealed. Intratracheal infusion of lipopolysaccharide (LPS, 10 mg/kg) induced ALI in wild-type (WT) and S100A9 knockout mice. Multiomics analyses (transcriptomics and proteomics) were performed to investigate the potential mechanisms by which S100A9 exacerbates acute lung damage. Hematoxylin-eosin, Giemsa, and TUNEL staining were used to evaluate lung injury and cell apoptosis. LPS (10 µg/mL)-induced murine lung epithelial MLE-12 cells were utilized to mimic ALI and were modulated by S100A9 lentiviral transfection. The impact of S100A9 on cell apoptosis and inflammatory responses were identified using flow cytometry and PCR. The expression of interleukin (IL)-17-nuclear factor kappa B (NFκB)-caspase-3 signaling components was identified using western blotting. RESULTS: Six common DEGs (S100A9, S100A8, IFITM6, SAA3, CD177, and MMP9) were identified in the six datasets related to ALI in sepsis. Compared to WT sepsis mice, S100A9 knockout significantly alleviated LPS-induced ALI in mice, with reduced lung structural damage and inflammatory exudation, decreased exfoliated cell and protein content in the lung lavage fluid, and reduced apoptosis and necrosis of pulmonary epithelial cells. Transcriptomic analysis revealed that knocking out S100A9 significantly affected 123 DEGs, which were enriched in immune responses, defense responses against bacteria or lipopolysaccharides, cytokine-cytokine receptor interactions, and the IL-17 signaling pathway. Proteomic analysis revealed that S100A9 knockout alleviated muscle contraction dysfunction and structural remodeling in sepsis-induced ALI. Multiomics analysis revealed that S100A9 may be closely related to interferon-induced proteins with tetratricopeptide repeats and oligoadenylate synthase-like proteins. LPS decreased MLE12 cell activity, accompanied by high expression of S100A9. The expression of IL-17RA, pNFκB, and cleaved-caspase-3 were increased by S100A9 overexpression and reduced by S100A9 knockdown in LPS-stimulated MLE12 cells. S100A9 knockdown decreases transcription of apoptosis-related markers Bax, Bcl and caspase-3, alleviating LPS-induced apoptosis. CONCLUSIONS: S100A9 as a key biomarker of sepsis-induced acute lung injury, and exacerbates lung damage and epithelial cell apoptosis induced by LPS via the IL-17-NFκB-caspase-3 signaling pathway.


Assuntos
Lesão Pulmonar Aguda , Sepse , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Interleucina-17/metabolismo , Caspase 3/metabolismo , Lipopolissacarídeos/farmacologia , Proteômica , Lesão Pulmonar Aguda/induzido quimicamente , Pulmão/patologia , Transdução de Sinais , Camundongos Knockout , Sepse/patologia , Calgranulina B/genética , Calgranulina B/metabolismo
19.
J Med Chem ; 67(8): 6456-6494, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38574366

RESUMO

Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.


Assuntos
DNA , Descoberta de Drogas , Interleucina-17 , Bibliotecas de Moléculas Pequenas , Interleucina-17/metabolismo , Interleucina-17/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , DNA/metabolismo , DNA/química , Humanos , Animais , Relação Estrutura-Atividade , Ligação Proteica , Camundongos
20.
Immun Inflamm Dis ; 12(4): e1207, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38661103

RESUMO

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa, with a gradually increasing incidence. Therefore, it is necessary to actively seek targets for the treatment of UC. METHODS: Common differentially expressed genes (DEGs) were screened from two microarray data sets related to UC. Protein-protein interaction network was constructed to find the hub genes. The UC mouse model and cell model were induced by dextran sulfate sodium (DSS). The pathological changes of colon tissue were observed by hematoxylin-eosin staining. Immunohistochemistry and immunofluorescence were performed to detect the expressions of Ki67 and Claudin-1. The performance of mice was observed by disease activity index (DAI). The effect of TOP2A on proliferation, inflammation, oxidative stress, and interleukin-17 (IL-17) signaling pathway in UC model was measured by cell counting kit-8, enzyme-linked immunosorbent assay, and western blot. RESULTS: Through bioinformatics analysis, 295 common DEGs were screened, and the hub gene TOP2A was selected. In UC model, there was obvious inflammatory cell infiltration in the colon and less goblet cells, while si-TOP2A lessened it. More Ki67 positive cells and less Claudin-1 positive cells were observed in UC model mice. Furthermore, knockdown of TOP2A increased the body weight and colon length of UC mice, while the DAI was decreased. Through in vivo and in vitro experiments, knockdown of TOP2A also inhibited inflammation and IL-17 signaling pathway, and promoted proliferation in DSS-induced NCM460 cells. CONCLUSION: Knockdown of TOP2A alleviated the progression of UC by suppressing inflammation and inhibited IL-17 signaling pathway.


Assuntos
Colite Ulcerativa , DNA Topoisomerases Tipo II , Modelos Animais de Doenças , Progressão da Doença , Interleucina-17 , Proteínas de Ligação a Poli-ADP-Ribose , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Sulfato de Dextrana , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo II/genética , Técnicas de Silenciamento de Genes , Interleucina-17/metabolismo , Interleucina-17/genética , Mapas de Interação de Proteínas
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