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Aberrant activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway causes autoimmunity in humans and mice; however, the exact mechanism by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology is still not fully understood. Here, we used a cGAS knockin (KI) mouse model that develops systemic autoimmunity. In the lungs of cGAS-KI mice, blood vessels were enclosed by organized lymphoid tissues that resemble tertiary lymphoid structures (TLSs). Cell-intrinsic cGAS induction promoted up-regulation of CCR5 in CD8+ T cells and led to CCL5 production in vascular endothelial cells. Peripheral CD8+ T cells were recruited to the lungs and produced CXCL13 and interferon-γ. The latter triggered endothelial cell death, potentiated CCL5 production, and was essential for TLS establishment. Blocking CCL5 or CCR5, or depleting CD8+ T cells, impaired TLS formation. cGAS-mediated TLS formation also enhanced humoral and antitumor responses. These data demonstrate that cGAS signaling drives a specialized lymphoid structure that underlies autoimmune tissue pathology.
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Linfócitos T CD8-Positivos , Células Endoteliais , Nucleotidiltransferases , Estruturas Linfoides Terciárias , Animais , Nucleotidiltransferases/imunologia , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Camundongos , Células Endoteliais/imunologia , Estruturas Linfoides Terciárias/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiocina CCL5/imunologia , Quimiocina CCL5/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/imunologia , Receptores CCR5/imunologia , Receptores CCR5/genética , Receptores CCR5/metabolismo , Autoimunidade/imunologiaRESUMO
HMGB1 (high-mobility group box-1) has been extensively studied as a damage-associated molecular pattern, with secreted cytokine function. However, its regulation on T cells, especially the function in the nucleus, has not been elucidated. Here, we use conditional knockout (HMGB1-f/f; CD2-cre) mice and find that HMGB1 potentiates the proliferation and interferon gamma (IFN-γ) expression of CD8 T cells rather than CD4 T cells. Notably, nuclear, but not secreted, HMGB1 supports the expression of IFN-γ in CD8 T cells via directly regulating the activity of Eomes, the transcription factor for IFN-γ. Functional study shows that HMGB1 promotes the anti-tumor ability of CD8 T cells in vitro and in vivo. Finally, tumor environmental interleukin-7 promotes HMGB1 and IFN-γ production via fatty acid oxidation in CD8 T cells. Overall, we identify the role of nuclear HMGB1 in CD8 T cell differentiation and demonstrate that it plays an important role in the anti-tumor programs of CD8 T cells.
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Inflammatory bowel disease (IBD) has high prevalence in Western counties. The high fat content in Western diets is one of the leading causes for this prevalence; however, the underlying mechanisms have not been fully defined. Here, we find that high-fat diet (HFD) induces ferroptosis of intestinal regulatory T (Treg) cells, which might be the key initiating step for the disruption of immunotolerance and the development of colitis. Compared with effector T cells, Treg cells favor lipid metabolism and prefer polyunsaturated fatty acids (PUFAs) for the synthesis of membrane phospholipids. Therefore, consumption of HFD, which has high content of PUFAs such as arachidonic acid, cultivates vulnerable Tregs that are fragile to lipid peroxidation and ferroptosis. Treg-cell-specific deficiency of GPX4, the key enzyme in maintaining cellular redox homeostasis and preventing ferroptosis, dramatically aggravates the pathogenesis of HFD-induced IBD. Taken together, these studies expand our understanding of IBD etiology.
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Rosacea patients show facial hypersensitivity to stimulus factors (such as heat and capsaicin); however, the underlying mechanism of this hyperresponsiveness remains poorly defined. Here, we show capsaicin stimulation in mice induces exacerbated rosacea-like dermatitis but has no apparent effect on normal skin. Nociceptor ablation substantially reduces the hyperresponsiveness of rosacea-like dermatitis. Subsequently, we find that γδ T cells express Ramp1, the receptor of the neuropeptide CGRP, and are in close contact with these nociceptors in the skin. γδ T cells are significantly increased in rosacea skin lesions and can be further recruited and activated by neuron-secreted CGRP. Rosacea-like dermatitis is reduced in T cell receptor δ-deficient (Tcrd-/-) mice, and the nociceptor-mediated aggravation of rosacea-like dermatitis is also reduced in these mice. In vitro experiments show that CGRP induces IL17A secretion from γδ T cells by regulating inflammation-related and metabolism-related pathways. Finally, rimegepant, a CGRP receptor antagonist, shows efficacy in the treatment of rosacea-like dermatitis. In conclusion, our findings demonstrate a neuron-CGRP-γδT cell axis that contributes to the hyperresponsiveness of rosacea, thereby showing that targeting CGRP is a potentially effective therapeutic strategy for rosacea.
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Peptídeo Relacionado com Gene de Calcitonina , Capsaicina , Receptores de Antígenos de Linfócitos T gama-delta , Rosácea , Células Receptoras Sensoriais , Animais , Rosácea/imunologia , Camundongos , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Células Receptoras Sensoriais/metabolismo , Capsaicina/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/genética , Pele/patologia , Pele/imunologia , Pele/metabolismo , Interleucina-17/metabolismo , Interleucina-17/imunologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Dermatite/imunologia , Dermatite/metabolismo , Dermatite/patologia , Modelos Animais de Doenças , Masculino , Nociceptores/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Humanos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismoRESUMO
IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, Il27ra deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis.
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Interleucina-17 , Metabolismo dos Lipídeos , Mitocôndrias , Psoríase , Animais , Mitocôndrias/metabolismo , Camundongos , Psoríase/patologia , Psoríase/imunologia , Psoríase/metabolismo , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Inflamação/patologia , Inflamação/metabolismo , Pele/patologia , Pele/metabolismo , Pele/imunologia , Pele/efeitos dos fármacos , Modelos Animais de Doenças , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Transdução de Sinais , HumanosRESUMO
Accumulating evidence has revealed the gut bacteria dysbiosis and brain hippocampal functional and structural alterations in major depressive disorder (MDD). However, the potential relationship between the gut microbiota and hippocampal function alterations in patients with MDD is still very limited. Data of resting-state functional magnetic resonance imaging were acquired from 44 unmedicated MDD patients and 42 demographically matched healthy controls (HCs). Severn pairs of hippocampus subregions (the bilateral cornu ammonis [CA1-CA3], dentate gyrus (DG), entorhinal cortex, hippocampal-amygdaloid transition area, and subiculum) were selected as the seeds in the functional connectivity (FC) analysis. Additionally, fecal samples of participants were collected and 16S rDNA amplicon sequencing was used to identify the altered relative abundance of gut microbiota. Then, association analysis was conducted to investigate the potential relationships between the abnormal hippocampal subregions FC and microbiome features. Also, the altered hippocampal subregion FC values and gut microbiota levels were used as features separately or together in the support vector machine models distinguishing the MDD patients and HCs. Compared with HCs, patients with MDD exhibited increased FC between the left hippocampus (CA2, CA3 and DG) and right hippocampus (CA2 and CA3), and decreased FC between the right hippocampal CA3 and bilateral posterior cingulate cortex. In addition, we found that the level of proinflammatory bacteria (i.e., Enterobacteriaceae) was significantly increased, whereas the level of short-chain fatty acids producing-bacteria (i.e., Prevotellaceae, Agathobacter and Clostridium) were significantly decreased in MDD patients. Furthermore, FC values of the left hippocampal CA3- right hippocampus (CA2 and CA3) was positively correlated with the relative abundance of Enterobacteriaceae in patients with MDD. Moreover, altered hippocampal FC patterns and gut microbiota level were considered in combination, the best discrimination was obtained (AUC = 0.92). These findings may provide insights into the potential role of gut microbiota in the underlying neuropathology of MDD patients.
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Transtorno Depressivo Maior , Microbioma Gastrointestinal , Hipocampo , Imageamento por Ressonância Magnética , Humanos , Transtorno Depressivo Maior/microbiologia , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/diagnóstico por imagem , Masculino , Hipocampo/fisiopatologia , Hipocampo/diagnóstico por imagem , Hipocampo/microbiologia , Adulto , Feminino , Disbiose/microbiologia , Disbiose/fisiopatologia , Adulto Jovem , Estudos de Casos e Controles , Pessoa de Meia-Idade , Fezes/microbiologiaRESUMO
Thermogenic brown adipose tissue (BAT) has a positive impact on whole-body metabolism. However, in vivo mapping of BAT activity typically relies on techniques involving ionizing radiation, such as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) and computed tomography (CT). Here we report a noninvasive metabolic magnetic resonance imaging (MRI) approach based on creatine chemical exchange saturation transfer (Cr-CEST) contrast to assess in vivo BAT activity in rodents and humans. In male rats, a single dose of the ß3-adrenoceptor agonist (CL 316,243) or norepinephrine, as well as cold exposure, triggered a robust elevation of the Cr-CEST MRI signal, which was consistent with the [18F]FDG PET and CT data and 1H nuclear magnetic resonance measurements of creatine concentration in BAT. We further show that Cr-CEST MRI detects cold-stimulated BAT activation in humans (both males and females) using a 3T clinical scanner, with data-matching results from [18F]FDG PET and CT measurements. This study establishes Cr-CEST MRI as a promising noninvasive and radiation-free approach for in vivo mapping of BAT activity.
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Tecido Adiposo Marrom , Imageamento por Ressonância Magnética , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/metabolismo , Animais , Masculino , Ratos , Imageamento por Ressonância Magnética/métodos , Humanos , Feminino , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Temperatura Baixa , Termogênese , Creatina/metabolismo , AdultoRESUMO
Systemic sclerosis (SSc) poses a significant challenge in autoimmunology, characterized by the development of debilitating fibrosis of skin and internal organs. The pivotal role of dysregulated T cells, notably the skewed polarization toward Th2 cells, has been implicated in the vascular damage and progressive fibrosis observed in SSc. In this study, we explored the underlying mechanisms by which cannabinoid receptor 2 (CB2) highly selective agonist HU-308 restores the imbalance of T cells to alleviate SSc. Using a bleomycin-induced SSc (BLM-SSc) mouse model, we demonstrated that HU-308 effectively attenuates skin and lung fibrosis by specifically activating CB2 on CD4+ T cells to inhibit the polarization of Th2 cells in BLM-SSc mice, which was validated by Cnr2-specific-deficient mice. Different from classical signaling downstream of G protein-coupled receptors (GPCRs), HU-308 facilitates the expression of SOCS3 protein and subsequently impedes the IL2/STAT5 signaling pathway during Th2 differentiation. The deficiency of SOCS3 partially mitigated the impact of HU-308. Analysis of a cohort comprising 80 SSc patients and 82 healthy controls revealed an abnormal elevation in the Th2/Th1 ratio in SSc patients. The proportion of Th2 cells showed a significant positive correlation with mRSS score and positivity of anti-Scl-70. Administration of HU-308 to PBMCs and peripheral CD4+ T cells from SSc patients led to the upregulation of SOCS3, which effectively suppressed the aberrantly activated STAT5 signaling pathway and the proportion of CD4+IL4+ T cells. In conclusion, our findings unveil a novel mechanism by which the CB2 agonist HU-308 ameliorates fibrosis in SSc by targeting and reducing Th2 responses. These insights provide a foundation for future therapeutic approaches in SSc by modulating Th2 responses.
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Diferenciação Celular , Modelos Animais de Doenças , Receptor CB2 de Canabinoide , Escleroderma Sistêmico , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas , Células Th2 , Animais , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Células Th2/imunologia , Camundongos , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Diferenciação Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Humanos , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Feminino , Janus Quinases/metabolismo , Masculino , Camundongos Knockout , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Bleomicina , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Pessoa de Meia-IdadeRESUMO
Immunoglobulin A nephropathy (IgAN) is a complex autoimmune disease with various underlying causes and significant clinical heterogeneity. There are large individual differences in its development, and the etiology and pathogenesis are still poorly understood. While it is known that immunobiological factors play a significant role in the pathophysiology of IgAN, the specific nature of these factors has yet to be fully elucidated. Numerous investigations have verified that cluster of differentiation 4+ (CD4+) and CD8+ T lymphocytes are involved in the immunopathogenesis of IgAN. Furthermore, certain data also point to γδT cells' involvement in the pathophysiology of IgAN. By thoroughly examining the mechanisms of action of these T cells in the context of IgAN, this review sheds light on the immunopathogenesis of the disease and its associated factors. The review is intended to provide reference value for the future research in this field and promising treatment clues for clinical patients.
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BACKGROUND: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. METHODS: The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA+ B cells. RESULTS: HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8+ T lymphocyte activation was enhanced in the absence of IL-21R due to the reduction of immunosuppressive IgA+ B cells. Mechanistically, the IL-21R-STAT1-c-Jun/c-Fos regulatory axis was activated in MASH-driven HCC and thus promoted the transcription of Igha, resulting in the induction of IgA+ B cells. CONCLUSIONS: IL-21R plays a cancer-promoting role by inducing IgA+ B cells in MASH-driven hepatocarcinogenesis. Targeting IL-21R signaling represents a potential therapeutic strategy for cancer therapy.
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Linfócitos B , Carcinoma Hepatocelular , Fígado Gorduroso , Imunoglobulina A , Neoplasias Hepáticas , Transdução de Sinais , Animais , Humanos , Masculino , Camundongos , Linfócitos B/metabolismo , Linfócitos B/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/etiologia , Regulação Neoplásica da Expressão Gênica , Imunoglobulina A/metabolismo , Subunidade alfa de Receptor de Interleucina-21/metabolismo , Subunidade alfa de Receptor de Interleucina-21/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Receptores de Interleucina-21/metabolismo , Receptores de Interleucina-21/genéticaRESUMO
Transarterial embolization, the first-line treatment for hepatocellular carcinoma, does not always lead to promising outcomes in all patients. A better understanding of how the immune lymphocyte changes after transarterial embolization might be the key to improve the efficacy of transarterial embolization. However, there are few studies evaluating immune lymphocytes in transarterial embolization patients. Therefore, we aimed to evaluate the short- and long-term effects of transarterial embolization on lymphocyte subsets in patients with hepatocellular carcinoma to identify those that predict transarterial embolization prognosis. Peripheral blood samples were collected from 44 patients with hepatocellular carcinoma at the following time points: 1 d before the initial transarterial embolization, 3 d after the initial transarterial embolization, and 1 mo after the initial transarterial embolization and subjected to peripheral blood mononuclear cell isolation and flow cytometry. Dynamic changes in 75 lymphocyte subsets were recorded, and their absolute counts were calculated. Tumor assessments were made every 4 to 6â wk via computed tomography or magnetic resonance imaging. Our results revealed that almost all lymphocyte subsets fluctuated 3 d after transarterial embolization, but only Tfh and B cells decreased 1 mo after transarterial embolization. Univariate and multivariate Cox regression showed that high levels of Th2 and conventional killer Vδ2 cells were associated with longer progressive-free survival after transarterial embolization. Longer overall survival after transarterial embolization was associated with high levels of Th17 and viral infection-specific Vδ1 cells and low levels of immature natural killer cells. In conclusion, transarterial embolization has a dynamic influence on the status of lymphocytes. Accordingly, several lymphocyte subsets can be used as prognostic markers for transarterial embolization.
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Carcinoma Hepatocelular , Embolização Terapêutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Embolização Terapêutica/métodos , Prognóstico , Idoso , Linfócitos/imunologia , Linfócitos/patologia , Subpopulações de Linfócitos/imunologia , Contagem de LinfócitosRESUMO
γδ T cells play a crucial role in immune surveillance and serve as a bridge between innate and adaptive immunity. However, the metabolic requirements and regulation of γδ T-cell development and function remain poorly understood. In this study, we investigated the role of liver kinase B1 (Lkb1), a serine/threonine kinase that links cellular metabolism with cell growth and proliferation, in γδ T-cell biology. Our findings demonstrate that Lkb1 is not only involved in regulating γδ T lineage commitment but also plays a critical role in γδ T-cell effector function. Specifically, T-cell-specific deletion of Lkb1 resulted in impaired thymocyte development and distinct alterations in γδ T-cell subsets in both the thymus and peripheral lymphoid tissues. Notably, loss of Lkb1 inhibited the commitment of Vγ1 and Vγ4 γδ T cells, promoted the maturation of IL-17-producing Vγ6 γδ T cells, and led to the occurrence of fatal autoimmune hepatitis (AIH). Notably, clearance of γδ T cells or blockade of IL-17 significantly attenuated AIH. Mechanistically, Lkb1 deficiency disrupted metabolic homeostasis and AMPK activity, accompanied by increased mTORC1 activation, thereby causing overactivation of γδ T cells and enhanced apoptosis. Interestingly, activation of AMPK or suppression of mTORC1 signaling effectively inhibited IL-17 levels and attenuated AIH in Lkb1-deficient mice. Our findings highlight the pivotal role of Lkb1 in maintaining the homeostasis of γδ T cells and preventing IL-17-mediated autoimmune diseases, providing new insights into the metabolic programs governing the subset determination and functional differentiation of thymic γδ T cells.
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Proteínas Quinases Ativadas por AMP , Hepatite Autoimune , Interleucina-17 , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases , Receptores de Antígenos de Linfócitos T gama-delta , Animais , Interleucina-17/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Hepatite Autoimune/imunologia , Hepatite Autoimune/patologia , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Knockout , Diferenciação Celular , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timo/imunologia , Timo/patologia , Transdução de Sinais , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismoRESUMO
Background: There are few research findings on the survival prognosis of spindle cell melanoma (SCM), which is an unusual kind of melanoma. The purpose of this study was to develop a thorough nomogram for predicting the overall survival (OS) of patients with SCM and to assess its validity by comparing it with the conventional American Joint Committee on Cancer (AJCC) staging system. Methods: The Surveillance, Epidemiology, and End Results database was searched, and 2,015 patients with SCM were selected for the analysis. The patients were randomly divided into training (n = 1,410) and validation (n = 605) cohorts by using R software. Multivariate Cox regression was performed to identify predictive factors. A nomogram was established based on these characteristics to predict OS in SCM. The calibration curve, concordance index (C-index), area under the receiver operating characteristic curve, and decision-curve analysis were utilized to assess the accuracy and reliability of the model. The net reclassification improvement and integrated discrimination improvement were also applied in this model to evaluate its differences with the AJCC model. Results: The developed nomogram suggests that race, AJCC stage, chemotherapy status, regional node examination status, marital status, and sex have the greatest effects on OS in SCM. The nomogram had a higher C-index than the AJCC staging system (0.751 versus 0.633 in the training cohort and 0.747 versus 0.650 in the validation cohort). Calibration plots illustrated that the model was capable of being calibrated. These criteria demonstrated that the nomogram outperforms the AJCC staging system alone. Conclusion: The nomogram developed in this study is sufficiently reliable for forecasting the risk and prognosis of SCM, which may facilitate personalized treatment recommendations in upcoming clinical trials.
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Melanoma , Nomogramas , Humanos , Melanoma/diagnóstico , Prognóstico , Reprodutibilidade dos Testes , PesquisaRESUMO
Primary Biliary Cholangitis (PBC) and Autoimmune Hepatitis (AIH) are autoimmune diseases that target hepatocytes and bile duct cells, respectively. Despite their shared autoimmune nature, the differences in immunologic characteristics between them remain largely unexplored. This study seeks to elucidate the unique immunological profiles of PBC and AIH, and to identify key differences. We comprehensively analyzed various T-cell subsets and their receptor expression in a cohort of 45 patients, including 27 PBC and 18 AIH cases. Both diseases exhibited T cell exhaustion and senescence along with a surge in inflammatory cytokines. Significantly increased CD38+HLA-DR+CD8+T cell populations were observed in both diseases. AIH was characterized by an upregulation of CD8+TEMRA, CD4+TEM, and CD4+TEMRA cells, and a concurrent reduction in Treg cells. In contrast, PBC displayed a pronounced presence of Tfh cells and a contraction of CD4-CD8-T cell populations. Correlation analysis revealed that NKP46+NK frequency was closely tied to ALT and AST levels, and TIGIT expression on T cells was associated with GLB level in AIH. In PBC, there is a significant correlation between Tfh cells and ALP levels. Moreover, the identified immune landscapes in both diseases strongly related to disease severity. Through logistic regression analysis, γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies emerged as distinct markers capable of differentiating PBC from AIH. In conclusion, our analyses reveal that PBC and AIH share similarities and differences regarding to immune profiles. And γδ T, TIGIT+Vδ2 T, and Tfh1 cell frequencies are potential noninvasive immunological markers that can differentiate PBC from AIH.
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Antibiotic-induced dysbiosis is a major risk factor for Clostridioides difficile infection (CDI), and fecal microbiota transplantation (FMT) is recommended for treating CDI. However, the underlying mechanisms remain unclear. Here, we show that Tritrichomonas musculis (T.mu), an integral member of the mouse gut commensal microbiota, reduces CDI-induced intestinal damage by inhibiting neutrophil recruitment and IL-1ß secretion, while promoting Th1 cell differentiation and IFN-γ secretion, which in turn enhances goblet cell production and mucin secretion to protect the intestinal mucosa. T.mu can actively metabolize arginine, not only influencing the host's arginine-ornithine metabolic pathway, but also shaping the metabolic environment for the microbial community in the host's intestinal lumen. This leads to a relatively low ornithine state in the intestinal lumen in C. difficile-infected mice. These changes modulate C. difficile's virulence and the host intestinal immune response, and thus collectively alleviating CDI. These findings strongly suggest interactions between an intestinal commensal eukaryote, a pathogenic bacterium, and the host immune system via inter-related arginine-ornithine metabolism in the regulation of pathogenesis and provide further insights for treating CDI.
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Clostridioides difficile , Infecções por Clostridium , Animais , Camundongos , Arginina , Ornitina , Intestinos/microbiologia , Transplante de Microbiota Fecal , Infecções por Clostridium/terapia , Infecções por Clostridium/microbiologiaRESUMO
Inflammation resolution is an essential process for preventing the development of chronic inflammatory diseases. However, the mechanisms that regulate inflammation resolution in psoriasis are not well understood. Here, we report that ANKRD22 is an endogenous negative orchestrator of psoriasiform inflammation because ANKRD22-deficient mice are more susceptible to IMQ-induced psoriasiform inflammation. Mechanistically, ANKRD22 deficiency leads to excessive activation of the TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, resulting in the hyperproduction of IL-23 in DCs. This is due to ANKRD22 being a negative feedback regulator for NIK because it physically binds to and assists in the degradation of accumulated NIK. Clinically, ANKRD22 is negatively associated with IL-23A expression and psoriasis severity. Of greater significance, subcutaneous administration of an AAV carrying ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Our findings suggest ANKRD22, an endogenous supervisor of NIK, is responsible for inflammation resolution in psoriasis, and may be explored in the context of psoriasis therapy.
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Modelos Animais de Doenças , Interleucina-23 , Psoríase , Transdução de Sinais , Psoríase/metabolismo , Psoríase/patologia , Psoríase/terapia , Psoríase/etiologia , Psoríase/imunologia , Psoríase/genética , Psoríase/induzido quimicamente , Animais , Camundongos , Interleucina-23/metabolismo , Interleucina-23/genética , Humanos , Inflamação/metabolismo , Inflamação/patologia , Camundongos Knockout , Pele/patologia , Pele/metabolismo , Quinase Induzida por NF-kappaB , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , NF-kappa B/metabolismoRESUMO
Oxabornyl polyenes represent a unique group of polyketides characterized by a central polyene core flanked by a conserved oxabornyl moiety and a structurally diverse oxygen heterocyclic ring. They are widely distributed in fungi and possess a variety of biological activities. Due to the significant spatial separation between the two stereogenic ring systems, it is difficult to establish their overall relative configurations. Here, we isolated three oxabornyl polyenes, prugosenes A1-A3 (1-3), from Talaromyces sp. JNU18266-01. Although these compounds were first reported from Penicillium rugulosum, their overall relative and absolute configurations remained unassigned. By employing ozonolysis in combination with ECD calculations, we were able to establish their absolute configurations, and additionally obtained seven new chemical derivatives (4-10). Notably, through NMR data analysis and quantum chemical calculations, we achieved the structural revision of prugosene A2. Furthermore, prugosenes A1-A3 exhibited potent antiviral activity against the respiratory syncytial virus, with compound 1 displaying an IC50 value of 6.3 µM. Our study thus provides a valuable reference for absolute configuration assignment of oxabornyl polyene compounds.
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Polienos , Polienos/química , Polienos/farmacologia , Estrutura Molecular , Talaromyces/química , Antivirais/farmacologia , Antivirais/química , Vírus Sinciciais Respiratórios/efeitos dos fármacos , HumanosRESUMO
Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nitrofuranos , Animais , Camundongos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Antígeno B7-H1 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , HidroxibenzoatosRESUMO
Iron metabolism plays a crucial role in cell viability, but its relationship with adult stem cells and cancer stem cells is not fully understood. The ferritin complex, responsible for intracellular iron storage, is important in this process. We report that conditional deletion of ferritin heavy chain 1 (Fth1) in the hematopoietic system reduced the number and repopulation capacity of hematopoietic stem cells (HSCs). These effects were associated with a decrease in cellular iron level, leading to impaired mitochondrial function and the initiation of apoptosis. Iron supplementation, antioxidant, and apoptosis inhibitors reversed the reduced cell viability of Fth1-deleted hematopoietic stem and progenitor cells (HSPCs). Importantly, leukemic stem cells (LSCs) derived from MLL-AF9-induced acute myeloid leukemia (AML) mice exhibited reduced Fth1 expression, rendering them more susceptible to apoptosis induced by the iron chelation compared to normal HSPCs. Modulating FTH1 expression using mono-methyl fumarate increased LSCs resistance to iron chelator-induced apoptosis. Additionally, iron supplementation, antioxidant, and apoptosis inhibitors protected LSCs from iron chelator-induced cell death. Fth1 deletion also extended the survival of AML mice. These findings unveil a novel mechanism by which ferritin-mediated iron homeostasis regulates the survival of both HSCs and LSCs, suggesting potential therapeutic strategies for blood cancer with iron dysregulation.