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Background The early growth response 1 (EGR1) is a central transcription factor involved in systemic sclerosis (SSc) pathogenesis. Iguratimod is a synthesized anti-rheumatic disease-modifying drug, which shows drastic inhibition to EGR1 expression in B cells. This study is aiming to investigate the anti-fibrotic effect of iguratimod in SSc. Methods EGR1 was detected by immunofluorescence staining real-time PCR or western blot. Iguratimod was applied in EGR1 overexpressed or knockdown human dermal fibroblast, bleomycin pre-treated mice, tight skin 1 mice, and SSc skin xenografts. RNA sequencing was performed in cultured fibroblast and xenografts to identify the iguratimod regulated genes. Results EGR1 overexpressed predominantly in non-immune cells of SSc patients. Iguratimod reduced EGR1 expression in fibroblasts and neutralized changes of EGR1 response genes regulated by TGFβ. The extracellular matrix (ECM) production and activation of fibroblasts were attenuated by iguratimod while EGR1 overexpression reversed this effect of iguratimod. Iguratimod ameliorated the skin fibrosis induced by bleomycin and hypodermal fibrosis in TSK-1 mice. Decreasing in the collagen content as well as the density of EGR1 or TGFβ positive fibroblasts of skin xenografts from naïve SSc patients was observed after local treatment of iguratimod. Conclusion Targeting EGR1 expression is a probable underlying mechanism for the anti-fibrotic effect of iguratimod.

Follicular helper T (Tfh) cells are the specialized CD4 T cell subset that supports B cells to produce high-affinity antibodies and generate humoral memory. Not only is the function of Tfh cells instrumental to mount protect antibodies but also to support autoantibody production and promote systemic inflammation in autoimmune diseases. However, it remains unclear how the activation of Tfh cells is driven in autoimmune diseases. Here, we report that in patients with rheumatoid arthritis (RA), excessive generation of CXCR5 PD-1 memory Tfh cells was observed and the frequency of memory Tfh cells correlated with disease activity score calculator for RA (DAS28). The differentiation of Tfh cells is dependent on signal transducer and activator of transcription 3 (STAT3), the key transcription factor downstream of cytokine signal pathways. A drastic increase of phosphorylated STAT3 (pSTAT3) in CD4 T cells were detected in RA patients who also produced larger amounts of STAT3-stimulating cytokines, including IL-6, IL-21, IL-10, and leptin than those of healthy controls. Importantly, the phosphorylation status of STAT3 in CD4 T cells positively correlated with the plasma concentration of IL-6 and the frequency of memory Tfh cells. This study reveals an IL-6-pSTAT3-Tfh immunoregulatory axis in the pathogenesis of RA and reinforces its candidature as biomarkers and targets for diagnosis and therapy.

Objectives Rheumatoid arthritis (RA) is a disease characterised by bone destruction and systemic inflammation, and interleukin‐6 (IL‐6) is a therapeutic target for treating it. The study aimed at investigating the sources of IL‐6 and the influence of hypoxia‐inducible factor‐1α (HIF‐1α) on IL‐6 production by B cells in RA patients. Methods The phenotype of IL‐6‐producing cells in the peripheral blood of RA patients was analysed using flow cytometry. Bioinformatics, real‐time polymerase chain reaction, Western blot and immunofluorescence staining were used to determine the IL‐6 production and HIF‐1α levels in B cells. A dual‐luciferase reporter assay and chromatin immunoprecipitation were used to investigate the regulatory role of HIF‐1α on IL‐6 production in human and mouse B cells. Results Our findings revealed that B cells are major sources of IL‐6 in the peripheral blood of RA patients, with the proportion of IL‐6‐producing B cells significantly correlated with RA disease activity. The CD27−IgD+ naïve B cell subset was identified as the typical IL‐6‐producing subset in RA patients. Both HIF‐1α and IL‐6 were co‐expressed by B cells in the peripheral blood and synovium of RA patients, and HIF‐1α was found to directly bind to the IL6 promoter and enhance its transcription. Conclusion This study highlights the role of B cells in producing IL‐6 and the regulation of this production by HIF‐1α in patients with RA. Targeting HIF‐1α might provide a new therapeutic strategy for treating RA. This study reveals that the CD27‐IgD+ naive B cell subset is the predominant source of IL‐6 production in the peripheral blood of rheumatoid arthritis (RA) patients. Moreover, the proportion of IL‐6‐producing B cells is significantly correlated with the level of RA disease activity. Our findings indicate that hypoxia‐inducible factor 1a directly binds to the IL6 promoter and augments its transcription.

[This corrects the article DOI: 10.3389/fimmu.2018.01226.].

Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.

ObjectiveHepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy.DesignNeutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry.ResultsNeutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1+ dendritic cell activation and CD8+ T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8+ T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8+ T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs.ConclusionCXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-β, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-β. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-β, and is distracted from itself. Our understanding on the humoral immunity induced by SARS-CoV-2 is still lacking. Here the authors analyze B cell responses at the single cell level to find that, in severe COVID-19 patients, plasmablasts shift from IFN to TGFβ instruction to produce IgA antibodies that are not specific to dominant SARS-CoV-2 antigens.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) significantly impact patient outcomes and quality of life. Accurately predicting AECOPD occurrence remains essential for optimizing disease management, yet existing predictive models have notable limitations. A retrospective analysis was conducted on 878 patients with chronic obstructive pulmonary disease (COPD) at Zhujiang Hospital, encompassing comprehensive clinical data including demographic, biochemical, and pulmonary function parameters. Potential predictors were identified through univariate Cox regression, and the dataset was split into 7:3 training‐test sets. Ninety‐one machine learning algorithms were constructed to predict AECOPD, with performance compared via concordance index (C‐index) metrics. Model performance was evaluated using receiver operating characteristic curves, k ‐fold cross‐validation, and subgroup analyses based on disease severity, age, and gender. Five biochemical indicators (including fibrinogen and prothrombin time), six demographic characteristics (including smoking status and age), and three pulmonary function parameters were significantly associated with AECOPD risk. The integrated machine learning model, which combined stepwise Cox regression and random survival forest algorithms, exhibited superior predictive performance compared to traditional models ( p  < .05). Area under the curve, calibration curves, and decision curve analyses consistently confirmed the model's excellent predictive capacity. A high‐performance AECOPD risk score (AECOPD‐RS) prediction model integrating multidimensional clinical features was developed. The findings demonstrate that multi‐algorithm machine learning techniques significantly enhance AECOPD prediction accuracy and stability. Future validation through multicenter prospective studies and incorporation of additional biomarkers could further optimize individualized COPD management strategies.

Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens have been tested extensively for therapeutic vaccination in cancer, with mixed clinical results. Here, we present a cell-therapy platform based on mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. Cytokine-armed DCPs differentiated into conventional type-I DCs (cDC1) and suppressed tumor growth, including melanoma and autochthonous liver models, without the need for antigen loading or myeloablative host conditioning. Tumor response involved synergy between IL-12 and FLT3L and was associated with natural killer and T cell infiltration and activation, M1-like macrophage programming and ischemic tumor necrosis. Antitumor immunity was dependent on endogenous cDC1 expansion and interferon-γ signaling but did not require CD8 + T cell cytotoxicity. Cytokine-armed DCPs synergized effectively with anti-GD2 chimeric-antigen receptor (CAR) T cells in eradicating intracranial gliomas in mice, illustrating their potential in combination therapies.