RESUMEN

The chemokine receptor CXCR3 and its ligands (MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11) play a central role in the generation of cellular inflammation, both in the protective responses to invading pathogens, and in different pathological conditions associated with autoimmunity. It is worth noting that CXCR3 is highly expressed on innate and adaptive lymphocytes, as well as on various cell subsets that are localized in non-immune organs and tissues. Our review focuses exclusively on CXCR3-expressing T cells, including Th1, Th17.1, Tfh17, Tfh17.1, CXCR3+ Treg cells, and Tc1 CD8+ T cells. Currently, numerous studies have highlighted the role of CXCR3-dependent interactions in the coordination of inflammation in the peripheral tissues, both to increase recruitment of CD4+ and CD8+ T cells that upregulate inflammation, and also for recruitment of CXCR3+ T regulatory cells to dampen overexuberant responses. Understanding the role of CXCR3 and its ligands might help to apply them as new and effective therapeutic targets in a wide range of diseases.

Asunto(s)

Autoinmunidad , Receptores CXCR3 , Receptores CXCR3/metabolismo , Receptores CXCR3/inmunología , Humanos , Autoinmunidad/inmunología , Animales , Infecciones/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo

RESUMEN

Modulation of immune microenvironment is critical for inflammatory bowel disease (IBD) intervention. Epigallocatechin gallate (EGCG), as a natural low toxicity product, has shown promise in treating IBD. However, whether and how EGCG regulates the intestinal microenvironment is not fully understood. Here we report that EGCG lessens colitis by orchestrating Th1 polarization and self-amplification in a novel manner that required multilevel-regulated intestinal microecosystem. Mechanistically, EGCG activates GPR43 on IEC to inhibit Th1 polarization dependently of short chain fatty acid (SCFA)-producing gut microbiota. Inhibition of GPR43 activity weakens the protective effects of EGCG on colitis development. Moreover, we confirm that fecal SCFAs and/or intestinal GPR43 are limited in patients with colitis and are correlated with Th1 cell number. Taken together, our study reveals an intestinal microenvironment-dependent immunoregulatory effects of EGCG in treating IBD and provides insight into mechanisms of EGCG-based novel immunotherapeutic strategies for IBD.

Asunto(s)

Catequina , Colitis , Microbioma Gastrointestinal , Receptores Acoplados a Proteínas G , Células TH1 , Catequina/análogos & derivados , Catequina/farmacología , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Colitis/metabolismo , Colitis/tratamiento farmacológico , Colitis/inmunología , Células TH1/inmunología , Células TH1/efectos de los fármacos , Células TH1/metabolismo , Humanos , Modelos Animales de Enfermedad , Ácidos Grasos Volátiles/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología

RESUMEN

BACKGROUND: Galectin-9 (Gal-9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. OBJECTIVES: To characterize the role and relevance of Gal-9 in the pathogenesis of CSU. METHODS: We assessed 60 CSU patients for their expression of Gal-9 on circulating eosinophils and basophils as well as T cell expression of the Gal-9 receptor TIM-3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal-9 expression by eosinophils and basophils. RESULTS: Our CSU patients had markedly increased rates of circulating Gal-9+ eosinophils and basophils and high numbers of lesional Gal-9+ cells. High rates of blood Gal-9+ eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF-α were positively correlated with circulating Gal-9+ eosinophils/basophils, and TNF-α markedly upregulated Gal-9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal-9+ eosinophils/basophils than non-responders, and omalizumab reduced blood levels of Gal-9+ eosinophils/basophils in responders. Gal-9+ eosinophils/basophils were negatively correlated with TIM-3+TH17 cells. CONCLUSION: Our findings demonstrate a previously unrecognized involvement of the Gal-9/TIM-3 pathway in the pathogenesis CSU and call for studies that explore its relevance.

Asunto(s)

Antialérgicos , Basófilos , Biomarcadores , Urticaria Crónica , Eosinófilos , Galectinas , Omalizumab , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Antialérgicos/uso terapéutico , Antialérgicos/farmacología , Basófilos/metabolismo , Basófilos/inmunología , Estudios de Casos y Controles , Urticaria Crónica/tratamiento farmacológico , Eosinófilos/metabolismo , Eosinófilos/inmunología , Galectinas/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Omalizumab/uso terapéutico , Omalizumab/farmacología , Índice de Severidad de la Enfermedad , Resultado del Tratamiento

RESUMEN

Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are high-incidence, non-melanoma skin cancers (NMSCs). The success of immune-targeted therapies in advanced NMSCs led us to anticipate that NMSCs harbored significant populations of tumor-infiltrating lymphocytes with potential anti-tumor activity. The main aim of this study was to characterize T cells infiltrating NMSCs. Flow cytometry and immunohistochemistry were used to assess, respectively, the proportions and densities of T cell subpopulations in BCCs (n = 118), SCCs (n = 33), and normal skin (NS, n = 30). CD8+ T cells, CD4+ T cell subsets, namely, Th1, Th2, Th17, Th9, and regulatory T cells (Tregs), CD8+ and CD4+ memory T cells, and γδ T cells were compared between NMSCs and NS samples. Remarkably, both BCCs and SCCs featured a significantly higher Th1/Th2 ratio (~four-fold) and an enrichment for Th17 cells. NMSCs also showed a significant enrichment for IFN-γ-producing CD8+T cells, and a depletion of γδ T cells. Using immunohistochemistry, NMSCs featured denser T cell infiltrates (CD4+, CD8+, and Tregs) than NS. Overall, these data favor a Th1-predominant response in BCCs and SCCs, providing support for immune-based treatments in NMSCs. Th17-mediated inflammation may play a role in the progression of NMSCs and thus become a potential therapeutic target in NMSCs.

Asunto(s)

Carcinoma Basocelular , Carcinoma de Células Escamosas , Linfocitos Infiltrantes de Tumor , Neoplasias Cutáneas , Células TH1 , Células Th17 , Humanos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Células Th17/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Células TH1/inmunología , Carcinoma Basocelular/inmunología , Carcinoma Basocelular/patología , Femenino , Masculino , Anciano , Estudios Transversales , Persona de Mediana Edad , Linfocitos T CD8-positivos/inmunología , Anciano de 80 o más Años , Adulto

RESUMEN

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with autoimmune mechanism of development. The investigation of neuroimmune interaction is one of the most developing directions in MS pathogenesis study. Catecholamines are direct mediators of this interaction and can be involved in the pathogenesis of MS by modulating cells of both innate and adaptive immune systems. The aim of this study was to investigate the influence of dopamine and norepinephrine on the ability of monocytes of patients with relapsing-remitting MS, to induce Th17- and Th1-immune response, which play a crucial role in the autoimmunity of the CNS. We found, that both dopamine and norepinephrine modulate the production of Th17- (IL-23, IL-1ß, and IL-6) and Th1-promoting (IL-12p70) cytokines by activated peripheral blood mononuclear cells or CD14+ monocytes in patients with MS and in healthy subjects. We also found the inhibitory effect of dopamine and norepinephrine on monocyte-induced production of IL-17 and IFN-γ by autologous CD4+ T-cells in both groups. Finally, the multidirectional role of D1- and D2-like dopaminergic receptors in the modulatory effect of dopamine on the ability of CD14+ monocytes to activate CD4+ T-cells was established, expanding the potential role of dopamine in the neuroimmune interaction.

Asunto(s)

Dopamina , Monocitos , Norepinefrina , Células TH1 , Células Th17 , Humanos , Dopamina/metabolismo , Monocitos/inmunología , Células TH1/inmunología , Células Th17/inmunología , Adulto , Masculino , Femenino , Norepinefrina/farmacología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Células Cultivadas , Citocinas/metabolismo , Citocinas/inmunología , Adulto Joven , Persona de Mediana Edad , Receptores de Dopamina D1/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Esclerosis Múltiple/inmunología , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/inmunología

RESUMEN

Introduction: Recently, more and more research illustrated the importance of inducing CD4+ T helper type (Th)-1 dominant immunity for the success of tumor immunotherapy. Our prior studies revealed the crucial role of CD4+ Th1 cells in orchestrating systemic and durable antitumor immunity, which contributes to the satisfactory outcomes of the novel cryo-thermal therapy in the B16F10 tumor model. However, the mechanism for maintaining the cryo-thermal therapy-mediated durable CD4+ Th1-dominant response remains uncovered. Additionally, cryo-thermal-induced early-stage CD4+ Th1-dominant T cell response showed a correlation with the favorable prognosis in patients with colorectal cancer liver metastasis (CRCLM). We hypothesized that CD4+ Th1-dominant differentiation induced during the early stage post cryo-thermal therapy would affect the balance of CD4+ subsets at the late phase. Methods: To understand the role of interferon (IFN)-γ, the major effector of Th1 subsets, in maintaining long-term CD4+ Th1-prone polarization, B16F10 melanoma model was established in this study and a monoclonal antibody was used at the early stage post cryo-thermal therapy for interferon (IFN)-γ signaling blockade, and the influence on the phenotypic and functional change of immune cells was evaluated. Results: IFNγ at the early stage after cryo-thermal therapy maintained long-lasting CD4+ Th1-prone immunity by directly controlling Th17, Tfh, and Tregs polarization, leading to the hyperactivation of Myeloid-derived suppressor cells (MDSCs) represented by abundant interleukin (IL)-1ß generation, and thereby further amplifying Th1 response. Discussion: Our finding emphasized the key role of early-phase IFNγ abundance post cryo-thermal therapy, which could be a biomarker for better prognosis after cryo-thermal therapy.

Asunto(s)

Diferenciación Celular , Crioterapia , Interferón gamma , Células TH1 , Animales , Femenino , Ratones , Diferenciación Celular/inmunología , Línea Celular Tumoral , Interferón gamma/metabolismo , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Ratones Endogámicos C57BL , Células TH1/citología , Células TH1/inmunología

RESUMEN

Background: It is well-known that TH1 and Treg cells exert anti- and pro-tumorigenic activity, respectively. Thus, TH1 cell suppression together with Treg cell hyperactivation contribute to tumor development. Glycyrrhiza glabra (G. glabra) has various immunomodulatory and anti-tumorigenic properties. Objective: To explore the impacts of G. glabra extract on different parameters related to TH1 and Treg cells using a breast cancer (BC) model. Methods: Four groups of Balb/C mice bearing 4T1 cell-induced BC were treated intraperitoneally with either saline or G. glabra extract at dosages of 50, 100 and 150 mg/kg (G. glabra-50, G. glabra-100, and G. glabra-150, respectively). After sacrificing animals on day 26, the frequency of splenic TH1 and Treg cells, the levels of serum IFN-γ, TGF-ß, and IL-12, and intra-tumoral expressions of granzyme-B, T-bet, and FOXP3 were assessed. Results: Compared to untreated tumor control (UTC) group, treatment with G. glabra-50, G. glabra-100, or G. glabra-150 increased the survival rate, percentage of TH1 cells, and T-bet expression. Conversely, they reduced the percentage of Treg cells, and serum TGF-ß levels. In comparison to the UTC group, treatment with G. glabra-50 and G. glabra-150 increased the serum IL-12 levels. Treatment with G. glabra-100 and G. glabra-150 boosted granzyme-B expression. Treatment with G. glabra-150 elevated IFN-γ levels, while treatment with G. glabra-50 decreased the FOXP3 expression. IL-12 levels were higher in mice treated with G. glabra-150 compared to those treated with G. glabra-100. Conclusion: Treatment of mice with BC using G. glabra extract improved survival rate, reduced tumor growth, and modulated T cell-mediated immune responses.

Asunto(s)

Neoplasias de la Mama , Modelos Animales de Enfermedad , Glycyrrhiza , Extractos Vegetales , Linfocitos T Reguladores , Células TH1 , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Femenino , Ratones , Células TH1/inmunología , Células TH1/efectos de los fármacos , Glycyrrhiza/química , Extractos Vegetales/farmacología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Ratones Endogámicos BALB C , Humanos , Citocinas/metabolismo , Inmunomodulación/efectos de los fármacos

RESUMEN

Bacopa monnieri (L) Wettst, commonly known as Brahmi, stands as a medicinal plant integral to India's traditional medical system, Ayurveda, where it is recognized as a "medhya rasayana"-a botanical entity believed to enhance intellect and mental clarity. Its significant role in numerous Ayurvedic formulations designed to address conditions such as anxiety, memory loss, impaired cognition, and diminished concentration underscores its prominence. Beyond its application in cognitive health, Brahmi has historically been employed in Ayurvedic practices for the treatment of inflammatory diseases, including arthritis. In contemporary biomedical research, Bacopa monnieri can attenuate the release of pro-inflammatory cytokines TNF-α and IL-6 in animal models. However, there remains a paucity of information regarding Bacopa's potential as an anticancer agent, warranting further investigation in this domain. Based on previous findings with Brahmi (Bacopa monnieri), the current study aims to find out the role of Brahmi plant preparation (BPP) in immunomodulatory actions on IDC. Employing a specific BPP concentration, we conducted a comprehensive study using MTT assay, ELISA, DNA methylation analysis, Western blotting, ChIP, and mRNA profiling to assess BPP's immunomodulatory properties. Our research finding showed the role of BPP in augmenting the action of T helper 1 (TH1) cells which secreted interferon-γ (IFN-γ) which in turn activated cytotoxic T-lymphocytes (CTL) to kill the cells of IDC (*p < 0.05). Moreover, we found out that treatment with BPP not only increased the activities of tumor-suppressor genes (p53 and BRCA1) but also decreased the activities of oncogenes (Notch1 and DNAPKcs) in IDC (*p < 0.05). BPP had an immense significance in controlling the epigenetic dysregulation in IDC through the downregulation of Histone demethylation & Histone deacetylation and upregulation of Histone methylation and Histone acetylation (*p < 0.05). Our Chromatin immunoprecipitation (ChIP)-qPCR data showed BPP treatment increased percentage enrichment of STAT1 & BRCA1 (*p < 0.05) and decreased percentage enrichment of STAT3, STAT5 & NF ΚB (*p < 0.05) on both TBX21 and BRCA1 gene loci in IDC. In addition, BPP treatment reduced the hypermethylation of the BRCA1-associated-DNA, which is believed to be a major factor in IDC (*p < 0.05). BPP not only escalates the secretion of type 1 specific cytokines but also escalates tumor suppression and harmonizes various epigenetic regulators and transcription factors associated with Signal Transducer and Activator of Transcription (STAT) to evoke tumor protective immunity in IDC.

Asunto(s)

Bacopa , Carcinoma Ductal , Neoplasias , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Histonas , Citocinas

RESUMEN

The immune mechanism underlying hepatitis B surface antigen (HBsAg) loss, particularly type I inflammatory response, during pegylated interferon-α (PEG-IFN) therapy remains unclear. In this study, we aimed to elucidate such immune mechanisms. Overall, 82 patients with chronic hepatitis B (CHB), including 41 with HBsAg loss (cured group) and 41 uncured patients, received nucleos(t)ide analogue and PEG-IFN treatments. Blood samples from all patients, liver tissues from 14 patients with CHB, and hepatic perfusate from 8 liver donors were collected for immune analysis. Jurkat, THP-1 and HepG2.2.15 cell lines were used in cell experiments. The proportion of IFN-γ+ Th1 cells was higher in the cured group than in the uncured group, which was linearly correlated with HBsAg decline and alanine aminotransferase (ALT) levels during treatment. However, CD8+ T cells were weakly associated with HBsAg loss. Serum and intrahepatic levels of Th1 cell-associated chemokines (C-X-C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11, IFN-γ) were significantly lower in the cured patients than in patients with a higher HBsAg quantification during therapy. Serum from cured patients induced more M1 (CD68+CD86+ macrophage) cells than that from uncured patients. Patients with chronic HBV infection had significantly lower proportions of CD86+ M1 and CD206+ M2 macrophages in their livers than healthy controls. M1 polarization of intrahepatic Kupffer cells promoted HBsAg loss by upregulating the effector function of tissue-resident memory T cells with increased ALT levels. IFN-γ+ Th1 activates intrahepatic resident memory T cells to promote HBsAg loss by inducing M1 macrophage polarization.

Asunto(s)

Antígenos de Superficie de la Hepatitis B , Hepatitis B Crónica , Hígado , Macrófagos , Células T de Memoria , Células TH1 , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antivirales/uso terapéutico , Antivirales/farmacología , Antígenos de Superficie de la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa , Interferón gamma , Hígado/inmunología , Macrófagos/inmunología , Células T de Memoria/inmunología , Células TH1/inmunología

RESUMEN

Multifunctional CD4+ T helper 1 (Th1) cells, producing IFN-γ, TNF-α and IL-2, define a correlate of vaccine-mediated protection against intracellular infection. In our previous study, we found that CVC1302 in oil formulation promoted the differentiation of IFN-γ+/TNF-α+/IL-2+Th1 cells. In order to extend the application of CVC1302 in oil formulation, this study aimed to elucidate the mechanism of action in improving the Th1 immune response. Considering the signals required for the differentiation of CD4+ T cells to Th1 cells, we detected the distribution of innate immune cells and the model antigen OVA-FITC in lymph node (LN), as well as the quantity of cytokines produced by the innate immune cells. The results of these experiments show that, cDC2 and OVA-FITC localized to interfollicular region (IFR) of the draining lymph nodes, inflammatory monocytes localized to both IFR and T cell zone, which mainly infiltrate from the blood. In this inflammatory niche within LN, CD4+ T cells were attracted into IFR by CXCL10, secreted by inflammatory monocytes, then activated by cDC2, secreting IL-12. Above all, CVC1302 in oil formulation, on the one hand, targeted antigen and inflammatory monocytes into the LN IFR in order to attract CD4+ T cells, on the other hand, targeted cDC2 to produce IL-12 in order to promote optimal Th1 differentiation. The new finding will provide a blueprint for application of immunopotentiators in optimal formulations.

Asunto(s)

Citocinas , Células Dendríticas , Inmunización , Células TH1 , Animales , Ratones , Células Dendríticas/inmunología , Células TH1/inmunología , Citocinas/metabolismo , Ganglios Linfáticos/inmunología , Diferenciación Celular/efectos de los fármacos , Ovalbúmina/inmunología , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Femenino , Activación de Linfocitos/inmunología , Activación de Linfocitos/efectos de los fármacos , Aceites/química , Ratones Endogámicos C57BL

RESUMEN

BACKGROUND: The experimental autoimmune myocarditis (EAM) model is valuable for investigating myocarditis pathogenesis. M1-type macrophages and CD4+T cells exert key pathogenic effects on EAM initiation and progression. Baicalein (5,6,7-trihydroxyflavone, C15H10O5, BAI), which is derived from the Scutellaria baicalensis root, is a primary bioactive compound with potent anti-inflammatory and antioxidant properties. BAI exerts good therapeutic effects against various autoimmune diseases; however, its effect in EAM has not been thoroughly researched. PURPOSE: This study aimed to explore the possible inhibitory effect of BAI on M1 macrophage polarisation and CD4+T cell differentiation into Th1 cells via modulation of the JAK-STAT1/4 signalling pathway, which reduces the secretion of pro-inflammatory factors, namely, TNF-α and IFN-γ, and consequently inhibits TNF-α- and IFN-γ-triggered apoptosis in cardiomyocytes of the EAM model mice. STUDY DESIGN AND METHODS: Flow cytometry, immunofluorescence, real-time quantitative polymerase chain reaction (q-PCR), and western blotting were performed to determine whether BAI alleviated M1/Th1-secreted TNF-α- and IFN-γ-induced myocyte death in the EAM model mice through the inhibition of the JAK-STAT1/4 signalling pathway. RESULTS: These results indicate that BAI intervention in mice resulted in mild inflammatory infiltrates. BAI inhibited JAK-STAT1 signalling in macrophages both in vivo and in vitro, which attenuated macrophage polarisation to the M1 type and reduced TNF-α secretion. Additionally, BAI significantly inhibited the differentiation of CD4+T cells to Th1 cells and IFN-γ secretion both in vivo and in vitro by modulating the JAK-STAT1/4 signalling pathway. This ultimately led to decreased TNF-α and IFN-γ levels in cardiac tissues and reduced myocardial cell apoptosis. CONCLUSION: This study demonstrates that BAI alleviates M1/Th1-secreted TNF-α- and IFN-γ-induced cardiomyocyte death in EAM mice by inhibiting the JAK-STAT1/4 signalling pathway.

Asunto(s)

Apoptosis , Modelos Animales de Enfermedad , Flavanonas , Interferón gamma , Quinasas Janus , Miocarditis , Miocitos Cardíacos , Factor de Transcripción STAT1 , Transducción de Señal , Factor de Necrosis Tumoral alfa , Animales , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Quinasas Janus/metabolismo , Ratones , Flavanonas/farmacología , Masculino , Interferón gamma/metabolismo , Apoptosis/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Miocarditis/tratamiento farmacológico , Factor de Transcripción STAT4/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Ratones Endogámicos BALB C , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Scutellaria baicalensis/química , Células TH1/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos

RESUMEN

BACKGROUND: Although Hashimoto's thyroiditis (HT) is one of most common autoimmune thyroid diseases, its treatment remains focused on symptom relief. The soluble epoxide hydrolase (sEH) shows potential functions as a drug target in alleviating some autoimmune diseases; however, we seldom know its role in HT. METHODS: The protein expression of sEH and related downstream molecules were evaluated by immunohistochemistry, Western blotting, ELISA, or immunofluorescence staining. RNA sequencing of tissue samples was performed to analyze differential genes and dysregulated pathways in HT and controls. The thyroid follicular epithelial cells (TFECs) and rat HT model were used to verify the biological function of sEH and the inhibition role of adamantyl-ureido-dodecanoic acid (AUDA) in HT. RESULTS: The sEH was significantly upregulated in HT patients compared with healthy individuals. Transcriptome sequencing showed cytokine-related pathways and chemokine expression; especially chemokine CXCL10 and its receptor CXCR3 were aberrant in HT patients. In TFECs and a rat HT model, blocking sEH by AUDA inhibitor could effectively inhibit the autoantibody, proinflammatory nuclear kappa factor B (NF-κB) signaling, chemokine CXCL10/CXCR3 expression, and type-1 helper CD4+ T cells. CONCLUSION: Our findings suggest that sEH/NF-κB p65/CXCL10-CXCR3 might be promising therapeutic targets for HT.

Asunto(s)

Quimiocina CXCL10 , Epóxido Hidrolasas , Enfermedad de Hashimoto , Transducción de Señal , Factor de Transcripción ReIA , Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/metabolismo , Epóxido Hidrolasas/genética , Enfermedad de Hashimoto/metabolismo , Enfermedad de Hashimoto/tratamiento farmacológico , Enfermedad de Hashimoto/genética , Animales , Ratas , Humanos , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/genética , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIA/genética , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios de Casos y Controles , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Adamantano/análogos & derivados , Adamantano/farmacología , Adamantano/uso terapéutico , Células Epiteliales Tiroideas/metabolismo , Células Epiteliales Tiroideas/efectos de los fármacos

RESUMEN

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.

Asunto(s)

Glaucoma , Células Ganglionares de la Retina , Humanos , Ratones , Animales , Células Ganglionares de la Retina/patología , Molécula 1 de Adhesión Celular Vascular/metabolismo , Células TH1/patología , Glaucoma/metabolismo , Retina/patología , Trastornos de la Visión/patología , Modelos Animales de Enfermedad

RESUMEN

Myelin antigen-reactive Th1 and Th17 cells are critical drivers of central nervous system (CNS) autoimmune inflammation. Transcription factors T-bet and RORγt play a crucial role in the differentiation and function of Th1 and Th17 cells, and impart them a pathogenic role in CNS autoimmune inflammation. Mice deficient in these two factors do not develop experimental autoimmune encephalomyelitis (EAE). While T-bet and RORγt are known to regulate the expression of several cell adhesion and migratory molecules in T cells, their role in supporting Th1 and Th17 trafficking to the CNS is not completely understood. More importantly, once Th1 and Th17 cells reach the CNS, how the function of these transcription factors modulates the local inflammatory response during EAE is unclear. In the present study, we showed that myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55)-specific Th1 cells deficient in RORγt could cross the blood-brain barrier (BBB) but failed to induce demyelination, apoptosis of neurons, and EAE. Pathogenic Th17 cell-derived cytokines GM-CSF, TNF-α, IL-17A, and IL-21 significantly increased the surface expression of IL-23R on neuronal cells. Furthermore, we showed that, in EAE, neurons in the brain and spinal cord express IL-23R. IL-23-IL-23R signaling in neuronal cells caused phosphorylation of STAT3 (Ser727 and Tyr705) and induced cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase-1 (PARP-1) molecules in an IL-23R-dependent manner and caused apoptosis. Thus, we provided a mechanism showing that T-bet is required to recruit pathogenic Th17 cells to the CNS and RORγt-mediated inflammatory response to drive the apoptosis of IL-23R+ neurons in the CNS and cause EAE. Understanding detailed molecular mechanisms will help to design better strategies to control neuroinflammation and autoimmunity. ONE SENTENCE SUMMARY: IL-23-IL-23R signaling promotes apoptosis of CNS neurons.

Asunto(s)

Encefalomielitis Autoinmune Experimental , Ratones , Animales , Células Th17 , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Ratones Transgénicos , Células TH1 , Inflamación , Glicoproteína Mielina-Oligodendrócito , Factores de Transcripción/metabolismo , Interleucina-23/metabolismo , Apoptosis , Neuronas/metabolismo , Neuronas/patología , Ratones Endogámicos C57BL

RESUMEN

Mesenchymal stem cells (MSCs) ameliorate graft-versus-host disease (GVHD)-induced tissue damage by exerting immunosuppressive effects. However, the related mechanism remains unclear. Here, we explored the therapeutic effect and mechanism of action of human placental-derived MSCs (hPMSCs) on GVHD-induced mouse liver tissue damage, which shows association with inflammatory responses, fibrosis accompanied by hepatocyte tight junction protein loss, the upregulation of Bax, and the downregulation of Bcl-2. It was observed in GVHD mice and Th1 cell differentiation system that hPMSCs treatment increased IL-10 levels and decreased TNF-α levels in the Th1 subsets via CD73. Moreover, hPMSCs treatment reduced tight junction proteins loss and inhibited hepatocyte apoptosis in the livers of GVHD mice via CD73. ADO level analysis in GVHD mice and the Th1 cell differentiation system showed that hPMSCs could also upregulate ADO levels via CD73. Moreover, hPMSCs enhanced Nrf2 expression and diminished Fyn expression via the CD73/ADO pathway in Th1, TNF-α+, and IL-10+ cells. These results indicated that hPMSCs promoted and inhibited the secretion of IL-10 and TNF-α, respectively, during Th1 cell differentiation through the CD73/ADO/Fyn/Nrf2 axis signaling pathway, thereby alleviating liver tissue injury in GVHD mice.

Asunto(s)

Enfermedad Injerto contra Huésped , Interleucina-10 , Embarazo , Humanos , Femenino , Animales , Ratones , Interleucina-10/metabolismo , Células TH1/metabolismo , Factor de Necrosis Tumoral alfa , Placenta/metabolismo , Factor 2 Relacionado con NF-E2 , Hígado/metabolismo

RESUMEN

Multiple myeloma (MM) is an incurable and recurrent malignancy characterized by abnormal plasma cell proliferation. There is an urgent need to develop effective drugs in MM. DCZ0825 is a small molecule compound derived from pterostilbene with direct anti-myeloma activity and indirect immune-killing effects though reversal of the immunosuppression. DCZ0825 inhibits the activity and proliferation of MM cells causing no significant toxicity to normal cells. Using flow cytometry, this study found that DCZ0825 induced caspase-dependent apoptosis in MM cells and arrested the cell cycle in the G2/M phase by down-regulating CyclinB1, CDK1 and CDC25. Moreover, DCZ0825 up-regulated IRF3 and IRF7 to increase IFN-γ, promoting M2 macrophages to transform into M1 macrophages, releasing the immunosuppression of CD4T cells and stimulated M1 macrophages and Th1 cells to secrete more INF-γ to form immune killing effect on MM cells. Treatment with DCZ0825 resulted in an increased proportion of positive regulatory cells such as CD4T, memory T cells, CD8T, and NK cells, with downregulation of the proportion of negative regulatory cells such as Treg cells and MDSCs. In conclusion, DCZ0825 is a novel compound with both antitumor and immunomodulatory activity.

Asunto(s)

Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Recurrencia Local de Neoplasia , Macrófagos , Células TH1 , Inmunomodulación

RESUMEN

Background: CD4 + Th1 cells producing IFN-γ are required to eradicate intracellular pathogens, however if uncontrolled these cells can cause immunopathology. The cytokine IL-10 is produced by multiple immune cells including Th1 cells during infection and regulates the immune response to minimise collateral host damage. In this study we aimed to elucidate the transcriptional network of genes controlling the expression of Il10 and proinflammatory cytokines, including Ifng in Th1 cells differentiated from mouse naive CD4 + T cells. Methods: We applied computational analysis of gene regulation derived from temporal profiling of gene expression clusters obtained from bulk RNA sequencing (RNA-seq) of flow cytometry sorted naïve CD4 + T cells from mouse spleens differentiated in vitro into Th1 effector cells with IL-12 and IL-27 to produce Ifng and Il10, compared to IL-27 alone which express Il10 only , or IL-12 alone which express Ifng and no Il10, or medium control driven-CD4 + T cells which do not express effector cytokines . Data were integrated with analysis of active genomic regions from these T cells using an assay for transposase-accessible chromatin with sequencing (ATAC)-seq, integrated with literature derived-Chromatin-immunoprecipitation (ChIP)-seq data and the RNA-seq data, to elucidate the transcriptional network of genes controlling expression of Il10 and pro-inflammatory effector genes in Th1 cells. The co-dominant role for the transcription factors, Prdm1 (encoding Blimp-1) and Maf (encoding c-Maf) , in cytokine gene regulation in Th1 cells, was confirmed using T cells obtained from mice with T-cell specific deletion of these transcription factors. Results: We show that the transcription factors Blimp-1 and c-Maf each have unique and common effects on cytokine gene regulation and not only co-operate to induce Il10 gene expression in IL-12 plus IL-27 differentiated mouse Th1 cells, but additionally directly negatively regulate key proinflammatory cytokines including Ifng, thus providing mechanisms for reinforcement of regulated Th1 cell responses. Conclusions: These data show that Blimp-1 and c-Maf positively and negatively regulate a network of both unique and common anti-inflammatory and pro-inflammatory genes to reinforce a Th1 response in mice that will eradicate pathogens with minimum immunopathology.

RESUMEN

The serine/threonine-specific Moloney murine leukemia virus (PIM) kinase family (i.e., PIM1, PIM2, and PIM3) has been extensively studied in tumorigenesis. PIM kinases are downstream of several cytokine signaling pathways that drive immune-mediated diseases. Uncontrolled T helper 17 (Th17) cell activation has been associated with the pathogenesis of autoimmunity. However, the detailed molecular function of PIMs in human Th17 cell regulation has yet to be studied. In the present study, we comprehensively investigated how the three PIMs simultaneously alter transcriptional gene regulation during early human Th17 cell differentiation. By combining PIM triple knockdown with bulk and scRNA-seq approaches, we found that PIM deficiency promotes the early expression of key Th17-related genes while suppressing Th1-lineage genes. Further, PIMs modulate Th cell signaling, potentially via STAT1 and STAT3. Overall, our study highlights the inhibitory role of PIMs in human Th17 cell differentiation, thereby suggesting their association with autoimmune phenotypes.

Asunto(s)

Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas c-pim-1 , Animales , Ratones , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/genética , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Transducción de Señal , Hematopoyesis , Diferenciación Celular , Células Th17/metabolismo

RESUMEN

Bullous pemphigoid (BP) is an organ-specific disease. Its pathogenesis has not been clearly studied yet; However, studies in recent years have shown that its pathogenesis is related to T helper cells. The pathogenesis of BP is mainly related to Th2 and Th17-related cytokines. IL-4, IL-5 and IL-13 cause eosinophil recruitment, promote antibody production, trigger pruritus and promote blister formation and other symptoms. IL-17 and IL-23 promote the production of matrix metalloproteinase-9 (MMP-9) by related cells, which causes dermo-epidermal junction (DEJ) separation to form bullae and blisters, and can persist in BP inflammation. The serum concentrations of IL-17 and IL-23 are related to the prognosis of BP. In this paper, we focus on the role of related cytokines in the pathogenesis of bullous pemphigoid and the relationship between the related cytokine populations secreted by three major T helper cells-helper T lymphocytes 1 (Th1), Th2, and Th17. A better understanding of the biological and immunological functions of cytokines associated with BP patients will provide opportunities for therapeutic targets in BP.

Asunto(s)

Penfigoide Ampolloso , Humanos , Citocinas , Interleucina-17 , Eosinófilos/patología , Inflamación/complicaciones , Interleucina-23

RESUMEN

[This corrects the article DOI: 10.3389/fimmu.2022.1054472.].