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Upon encountering allergens, CD4+ T cells differentiate into IL-4-producing Th2 cells in lymph nodes, which later transform into polyfunctional Th2 cells producing IL-5 and IL-13 in inflamed tissues. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of NRF2 in polyfunctional Th2 cells in murine models of allergic asthma and in human Th2 cells. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma and polyfunctional Th2 cells in vivo. Deletion of the ROS sensor NRF2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, NRF2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality independently of IL-33, partially by inducing PPARγ. Treatment with an NRF2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases.
Assuntos
Asma , Fator 2 Relacionado a NF-E2 , Células Th2 , Animais , Feminino , Humanos , Camundongos , Asma/imunologia , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinofilia/imunologia , Eosinofilia/metabolismo , Glicólise , Interleucina-33/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Fosforilação Oxidativa , PPAR gama/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
Somatic mutations in T cells can cause cancer but also have implications for immunological diseases and cell therapies. The mutation spectrum in nonmalignant T cells is unclear. Here, we examined somatic mutations in CD4+ and CD8+ T cells from 90 patients with hematological and immunological disorders and used T cell receptor (TCR) and single-cell sequencing to link mutations with T cell expansions and phenotypes. CD8+ cells had a higher mutation burden than CD4+ cells. Notably, the biggest variant allele frequency (VAF) of non-synonymous variants was higher than synonymous variants in CD8+ T cells, indicating non-random occurrence. The non-synonymous VAF in CD8+ T cells strongly correlated with the TCR frequency, but not age. We identified mutations in pathways essential for T cell function and often affected lymphoid neoplasia. Single-cell sequencing revealed cytotoxic TEMRA phenotypes of mutated T cells. Our findings suggest that somatic mutations contribute to CD8+ T cell expansions without malignant transformation.
Assuntos
Linfócitos T CD8-Positivos , Mutação , Receptores de Antígenos de Linfócitos T , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Adulto , Análise de Célula Única , Masculino , Feminino , Pessoa de Meia-Idade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Frequência do Gene , Fenótipo , IdosoRESUMO
Immunoregulatory mechanisms established in the lymphoid organs are vital for preventing autoimmunity. However, the presence of similar mechanisms in non-lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we find a negative association between psoriasis and fatty acid metabolism, as well as Th2 signature. Homeostatic expression of liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ) is essential for maintaining fatty acid metabolism and for conferring resistance to psoriasis in mice. Perturbation of signal transducer and activator of transcription 6 (STAT6) diminishes the homeostatic levels of LXR and PPARγ. Furthermore, mice lacking STAT6, interleukin 4 receptor alpha (IL-4Rα), or IL-13, but not IL-4, exhibit increased susceptibility to psoriasis. Under steady state, innate lymphoid cells (ILCs) are the primary producers of IL-13. In human skin, inhibiting tonic type 2 immunity exacerbates psoriasis-like inflammation and IL-17A, while activating LXR or PPARγ inhibits them. Hence, we propose that tonic type 2 immunity, driven by IL-13-producing ILCs, represents a crucial tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.
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Autoimunidade , Receptores X do Fígado , PPAR gama , Pele , Animais , Pele/imunologia , Pele/metabolismo , Pele/patologia , Humanos , Receptores X do Fígado/metabolismo , Camundongos , PPAR gama/metabolismo , Psoríase/imunologia , Psoríase/patologia , Psoríase/metabolismo , Camundongos Endogâmicos C57BL , Interleucina-13/metabolismo , Fator de Transcrição STAT6/metabolismo , Imunidade Inata , Masculino , Feminino , Linfócitos/imunologia , Linfócitos/metabolismoRESUMO
BCR::ABL1-independent pathways contribute to primary resistance to tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) and play a role in leukemic stem cell persistence. Here, we perform ex vivo drug screening of CML CD34+ leukemic stem/progenitor cells using 100 single drugs and TKI-drug combinations and identify sensitivities to Wee1, MDM2, and BCL2 inhibitors. These agents effectively inhibit primitive CD34+CD38- CML cells and demonstrate potent synergies when combined with TKIs. Flow-cytometry-based drug screening identifies mepacrine to induce differentiation of CD34+CD38- cells. We employ genome-wide CRISPR-Cas9 screening for six drugs, and mediator complex, apoptosis, and erythroid-lineage-related genes are identified as key resistance hits for TKIs, whereas the Wee1 inhibitor AZD1775 and mepacrine exhibit distinct resistance profiles. KCTD5, a consistent TKI-resistance-conferring gene, is found to mediate TKI-induced BCR::ABL1 ubiquitination. In summary, we delineate potential mechanisms for primary TKI resistance and non-BCR::ABL1-targeting drugs, offering insights for optimizing CML treatment.
Assuntos
Proteínas de Fusão bcr-abl , Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Sistemas CRISPR-Cas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Linhagem Celular TumoralRESUMO
Recently, there has been a notable rise in social and scientific interest regarding microplastic pollution in coasts where waves significantly influence flow patterns and material transport. This study explores typical short-term movement of buoyant microplastics driven by surf zone processes including wave transformation, breaking, and orbital motion. To track microplastics, Lagrangian Particle Tracking Model (PTM) coupled with Eulerian wave-current interaction model appropriate for coastal hydrodynamics was used. From the simulations, several important findings were observed. (i) In alongshore uniform beaches, lighter and larger buoyant microplastics tended to reach beach more readily. (ii) Accurate predictions of microplastic transport in the surf zone required the consideration of wave breaking. (iii) In alongshore non-uniform coastal bathymetry, rip-currents can send buoyant microplastics offshore, beyond the surf zone.
Assuntos
Microplásticos , Poluentes Químicos da Água , Plásticos , Poluentes Químicos da Água/análise , Monitoramento Ambiental , HidrodinâmicaRESUMO
Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. Among IL-23-sensing cells, we identified a subset of tumor-infiltrating regulatory T (Treg) cells that display a highly suppressive phenotype across mouse and human tumors. The use of three preclinical models of solid cancer in combination with genetic ablation of Il23r in Treg cells revealed that they are responsible for the tumor-promoting effect of IL-23. Mechanistically, we found that IL-23 sensing represents a crucial signal driving the maintenance and stabilization of effector Treg cells involving the transcription factor Foxp3. Our data support that targeting the IL-23/IL-23R axis in cancer may represent a means of eliciting antitumor immunity.
Assuntos
Interleucina-23 , Neoplasias , Animais , Humanos , Camundongos , Citocinas , Interleucina-23/genética , Neoplasias/genética , Linfócitos T , Microambiente TumoralRESUMO
BACKGROUND: In coronary computed tomography angiography (CCTA), the main issue of image quality is noise in obese patients, blooming artifacts due to calcium and stents, high-risk coronary plaques, and radiation exposure to patients. OBJECTIVE: To compare the CCTA image quality of deep learning-based reconstruction (DLR) with that of filtered back projection (FBP) and iterative reconstruction (IR). METHODS: This was a phantom study of 90 patients who underwent CCTA. CCTA images were acquired using FBP, IR, and DLR. In the phantom study, the aortic root and the left main coronary artery in the chest phantom were simulated using a needleless syringe. The patients were classified into three groups according to their body mass index. Noise, the signal-to-noise ratio (SNR), and the contrast-to-noise ratio (CNR) were measured for image quantification. A subjective analysis was also performed for FBP, IR, and DLR. RESULTS: According to the phantom study, DLR reduced noise by 59.8% compared to FBP and increased SNR and CNR by 121.4% and 123.6%, respectively. In a patient study, DLR reduced noise compared to FBP and IR. Furthermore, DLR increased the SNR and CNR more than FBP and IR. In terms of subjective scores, DLR was higher than FBP and IR. CONCLUSION: In both phantom and patient studies, DLR effectively reduced image noise and improved SNR and CNR. Therefore, the DLR may be useful for CCTA examinations.
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Liver X receptor (LXR) is a critical regulator of cholesterol homeostasis that inhibits T cell receptor (TCR)-induced proliferation by altering intracellular sterol metabolism. However, the mechanisms by which LXR regulates helper T cell subset differentiation remain unclear. Here, we demonstrate that LXR is a crucial negative regulator of follicular helper T (Tfh) cells in vivo. Both mixed bone marrow chimera and antigen-specific T cell adoptive cotransfer studies show a specific increase in Tfh cells among LXRß-deficient CD4+ T cell population in response to immunization and lymphocytic choriomeningitis mammarenavirus (LCMV) infection. Mechanistically, LXRß-deficient Tfh cells express augmented levels of T cell factor 1 (TCF-1) but comparable levels of Bcl6, CXCR5, and PD-1 in comparison with those of LXRß-sufficient Tfh cells. Loss of LXRß confers inactivation of GSK3ß induced by either AKT/Extracellular signal-regulated kinase (ERK) activation or Wnt/ß-catenin pathway, leading to elevated TCF-1 expression in CD4+ T cells. Conversely, ligation of LXR represses TCF-1 expression and Tfh cell differentiation in both murine and human CD4+ T cells. LXR agonist significantly diminishes Tfh cells and the levels of antigen-specific IgG upon immunization. These findings unveil a cell-intrinsic regulatory function of LXR in Tfh cell differentiation via the GSK3ß-TCF1 pathway, which may serve as a promising target for pharmacological intervention in Tfh-mediated diseases.
Assuntos
Células T Auxiliares Foliculares , Linfócitos T Auxiliares-Indutores , Camundongos , Humanos , Animais , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Centro Germinativo , Fator 1 de Transcrição de Linfócitos T/genética , Diferenciação CelularRESUMO
The photon counting detector (PCD) in computed tomography (CT) can count the number of incoming photons in order to obtain energy information for photons corresponding to user-defined thresholds. Research on the extraction of effective atomic number (EAN) and relative electron density (RED) using dual-energy CT (DECT) is currently underway. This study proposes a method for improving EAN and RED accuracy of tissue-equivalent materials by using PCD-CT-based stoichiometric calibration. After obtaining DECT images in energy bin (EB) and full spectrum (FS) modes for eight tissue-equivalent materials, the EAN was calculated with stoichiometric calibration. Using the EAN image, the RED image was acquired to evaluate the accuracy. The errors of both EAN and RED obtained with EB were within 4%. In particular, the accuracy of RED was higher than that of the FS method. Study results indicate that PCD-CT contributes to improving EAN and RED accuracy. Further studies will be aimed at reducing ring artifacts by pixel-correcting PCD images and improving stopping power ratio (SPR) measurements for dose calculation in particle therapy.
Assuntos
Elétrons , Tomografia Computadorizada por Raios X , Imagens de Fantasmas , Calibragem , Tomografia Computadorizada por Raios X/métodos , FótonsRESUMO
CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) is a rare subtype of T-LGLL with unknown etiology. In this study, we molecularly characterized a cohort of patients (n = 35) by studying their T-cell receptor (TCR) repertoire and the presence of somatic STAT5B mutations. In addition to the previously described gain-of-function mutations (N642H, Y665F, Q706L, S715F), we discovered six novel STAT5B mutations (Q220H, E433K, T628S, P658R, P702A, and V712E). Multiple STAT5B mutations were present in 22% (5/23) of STAT5B mutated CD4+ T-LGLL cases, either coexisting in one clone or in distinct clones. Patients with STAT5B mutations had increased lymphocyte and LGL counts when compared to STAT5B wild-type patients. TCRß sequencing showed that, in addition to large LGL expansions, non-leukemic T cell repertoires were more clonal in CD4+ T-LGLL compared to healthy. Interestingly, 25% (15/59) of CD4+ T-LGLL clonotypes were found, albeit in much lower frequencies, in the non-leukemic CD4+ T cell repertoires of the CD4+ T-LGLL patients. Additionally, we further confirmed the previously reported clonal dominance of TRBV6-expressing clones in CD4+ T-LGLL. In conclusion, CD4+ T-LGLL patients have a typical TCR and mutation profile suggestive of aberrant antigen response underlying the disease.
Assuntos
Leucemia Linfocítica Granular Grande , Linfócitos T CD4-Positivos , Mutação com Ganho de Função , Humanos , Leucemia Linfocítica Granular Grande/genética , Mutação , Fator de Transcrição STAT5/genéticaRESUMO
Dyslipidemia is a major cause of cardiovascular diseases which represent a leading cause of death in humans. Diverse immune cells are known to be involved in the pathogenesis of cardiovascular diseases such as atherosclerosis. Conversely, dyslipidemia is known to be tightly associated with immune disorders in humans, as evidenced by a higher incidence of atherosclerosis in patients with autoimmune diseases including psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. Given that the dyslipidemia-related autoimmune diseases are caused by autoreactive T cells and B cells, dyslipidemia seems to directly or indirectly regulate the adaptive immunity. Indeed, accumulating evidence has unveiled that proatherogenic factors can impact the differentiation and function of CD4+ T cells, CD8+ T cells, and B cells. This review discusses an updated overview on the regulation of adaptive immunity by dyslipidemia and proposes a potential therapeutic strategy for immune disorders by targeting lipid metabolism.
RESUMO
Large granular lymphocyte leukemia (LGLL) is characterized by somatic gain-of-function STAT3 mutations. However, the functional effects of STAT3 mutations on primary LGLL cells have not been studied in detail. In this study, we show that CD8+ T cells isolated from STAT3 mutated LGLL patients have high protein levels of epigenetic regulators, such as DNMT1, and are characterized by global hypermethylation. Correspondingly, treatment of healthy CD8+ T cells with IL-6, IL-15, and/or MCP-1 cytokines resulted in STAT3 activation, increased DNMT1, EZH2, c-MYC, l-MYC, MAX, and NFκB levels, increased DNA methylation, and increased oxidative stress. Similar results were discovered in KAI3 NK cells overexpressing gain-of-function STAT3Y640F and STAT3G618R mutants compared to KAI3 NK cells overexpressing STAT3WT. Our results also confirm that STAT3 forms a direct complex with DNMT1, EZH2, and HDAC1. In STAT3 mutated LGLL cells, DNA methyltransferase (DNMT) inhibitor azacitidine abrogated the activation of STAT3 via restored SHP1 expression. In conclusion, STAT3 mutations cause DNA hypermethylation resulting in sensitivity to DNMT inhibitors, which could be considered as a novel treatment option for LGLL patients with resistance to standard treatments.
Assuntos
Biomarcadores Tumorais/genética , Citocinas/metabolismo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Granular Grande/patologia , Mutação , Fator de Transcrição STAT3/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais , Células Tumorais CultivadasRESUMO
Pathogenic conversion of Th17 cells into multifunctional helper T cells or Th1 cells contributes to the pathogenesis of autoimmune diseases; however, the mechanism regulating the plasticity of Th17 cells remains unclear. Here, we found that Th17 cells expressed latent TGF-ß1 in a manner dependent on autocrine TGF-ß1. By employing IL-17-producing cell-specific Tgfb1 conditional knockout and fate-mapping systems, we demonstrated that TGF-ß1-deficient Th17 cells are relatively susceptible to becoming IFN-γ producers through IL-12Rß2 and IL-27Rα upregulation. TGF-ß1-deficient Th17 cells exacerbated tissue inflammation compared to TGF-ß1-sufficient Th17 cells in adoptive transfer models of experimental autoimmune encephalomyelitis and colitis. Thus, TGF-ß1 production by Th17 cells provides an essential autocrine signal for maintaining the stability and regulating the pathogenicity of Th17 cells in vivo.
Assuntos
Autoimunidade , Imunomodulação , Células Th17/imunologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Comunicação Autócrina , Biomarcadores , Colite/etiologia , Colite/metabolismo , Colite/patologia , Suscetibilidade a Doenças , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Regulação da Expressão Gênica , Imunofenotipagem , Contagem de Linfócitos , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fator de Crescimento Transformador beta1/genéticaRESUMO
The oncogenic protein Bcr-Abl has two major isoforms, p190Bcr-Abl and p210Bcr-Abl. While p210Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK). p190Bcr-Abl CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210Bcr-Abl, p190Bcr-Abl exhibited specific transcriptional upregulation of interferon, interleukin-1 receptor, and P53 signaling pathways, associated with hyperphosphorylation of relevant signaling molecules including JAK1/STAT1 and PAK1 in addition to Src hyperphosphorylation. Comparable to p190Bcr-Abl CML patients, p190Bcr-Abl cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190Bcr-Abl cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190Bcr-Abl CML and promising therapeutic targets for this high-risk patient group.
Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Transdução de Sinais/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica/métodos , Glucocorticoides/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Oncogenes/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteômica/métodos , Transcrição Gênica/genética , Regulação para Cima/genéticaRESUMO
Allergic asthma is a chronic inflammatory disease of the lung and the airway, which is characterized by aberrant type 2 immune responses to otherwise unharmful aeroallergens. While the central role of Th2 cells and type 2 cytokines in the pathogenesis of allergic asthma is well documented, the regulation and plasticity of Th2 cells remain incompletely understood. By using an animal model of allergic asthma in IL-4-reporter mice, we found that Th2 cells in the lung expressed higher levels of Rora than those in the lymph nodes, and that treatment with an RORα agonist SR1078 resulted in diminished Th2 cell responses in vivo. To determine the T cell-intrinsic role of RORα in allergic asthma in vivo, we established T cell-specific RORα-deficient (Cd4creRoraf/f) mice. Upon intranasal allergen challenges, Cd4creRoraf/f mice exhibited a significantly increased Th2 cells in the lungs and the airway and showed an enhanced eosinophilic inflammation compared to littermate control mice. Studies with Foxp3YFP-creRoraf/f mice and CD8+ T cell depletion showed that the increased Th2 cell responses in the Cd4creRoraf/f mice were independent of Treg cells and CD8+ T cells. Our findings demonstrate a critical regulatory role of RORα in Th2 cells, which suggest that RORα agonists could be effective for the treatment of allergic diseases.
Assuntos
Asma/tratamento farmacológico , Asma/imunologia , Benzamidas/farmacologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Administração Intranasal , Animais , Aspergillus oryzae , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Modelos Animais de Doenças , Interleucina-4/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Camundongos , OvalbuminaRESUMO
Hepatic hepcidin is a well-known major iron regulator and has been reported to be closely related to hepatitis C virus (HCV) replication. However, pharmacological targeting of the hepcidin in HCV replication has not been reported. A short-chain fatty acid, 4-Phenyl butyrate (4-PBA), is an acid chemical chaperone that acts as a histone deacetylase inhibitor (HDACi) to promote chromosomal histone acetylation. Here, we investigated the therapeutic effect of 4-PBA on hepcidin expression and HCV replication. We used HCV genotype 1b Huh 7.5-Con1 replicon cells and engraftment of NOD/SCID mice as in vitro and in vivo models to test the effect of 4-PBA. It was found that 4-PBA inhibited HCV replication in Huh7.5-Con1 replicon cells in a concentration- and time-dependent manner through the induction of hepcidin expression by epigenetic modification and subsequent upregulation of interferon-α signaling. HCV formed a membranous web composed of double-membrane vesicles and was utilized for RNA replication. Moreover, 4-PBA also disrupted the integrity of the membranous web and interfered with the molecular interactions critical for the assembly of the HCV replication complex. These findings suggest that 4-PBA is a key epigenetic inducer of anti-HCV hepatic hepcidin and might at least in part play a role in targeting host factors related to HCV infection as an attractive complement to current HCV therapies.
Assuntos
Epigênese Genética/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepcidinas/genética , Fenilbutiratos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Expressão Gênica/efeitos dos fármacos , Hepacivirus/genética , Hepacivirus/fisiologia , Hepatite C/prevenção & controle , Hepatite C/virologia , Hepcidinas/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Estrutura Molecular , Fenilbutiratos/química , Bibliotecas de Moléculas Pequenas/química , Replicação Viral/genéticaRESUMO
Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4+ T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n = 134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies.
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Doença Enxerto-Hospedeiro/genética , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/genética , Western Blotting , Proliferação de Células/genética , Proliferação de Células/fisiologia , Células HEK293 , Humanos , Imunidade Celular/genética , Imunidade Celular/fisiologia , Imunoprecipitação , Mutação/genética , Ligação Proteica/genética , Ligação Proteica/fisiologiaRESUMO
The incidence of atherosclerosis is higher among patients with several autoimmune diseases such as psoriasis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It is well documented that innate immune cells including macrophages and dendritic cells sense lipid species such as saturated fatty acids and oxidized low-density lipoprotein and produce pro-inflammatory cytokines and chemokines. However, whether a hyperlipidemic environment also impacts autoimmune T cell responses has been unclear. Among CD4+ T cells, Th17 and follicular helper T (Tfh) cells are known to play pathogenic roles in the development of hyperlipidemiaassociated autoimmune diseases. This review gives an overview of the cellular and molecular mechanisms by which dysregulated lipid metabolism impacts the pathogenesis of autoimmune diseases, with specific emphasis on Th17 and Tfh cells.
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Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Citocinas/imunologia , Metabolismo dos Lipídeos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/imunologia , Ácidos Graxos/imunologia , Ácidos Graxos/metabolismo , Humanos , Lipoproteínas LDL/imunologia , Lipoproteínas LDL/metabolismo , Macrófagos/citologia , Macrófagos/imunologia , Linfócitos T Auxiliares-Indutores/citologiaRESUMO
Unlike conventional 1H magnetic resonance imaging (MRI), 19F MRI features unambiguous detection of fluorine spins due to negligible background signals. Therefore, it is considered a promising noninvasive and selective imaging method for the diagnosis of cancers and other diseases. For 19F MRI, fluorine-rich molecules such as perfluorocarbons (PFC) have been formulated into nanoemulsions and used as its tracer agent. Along with advancements in other types of nanoparticles as targeted theranostics and stimuli-triggered probes and combined with the advantages of 19F MRI, PFC nanoemulsions are being empowered with these additional functionalities and becoming a promising theranostic platform. In this Review, we provide an overview of fluorine-based materials for sensitive 19F MRI of biological and pathological conditions. In particular, we describe designs and applications of recently reported stimuli-responsive and theranostic 19F MRI probes. Finally, challenges and future perspectives regarding the further development of 19F MRI probes for their clinical applications are described.