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关键词： TNBC   TRF2   cancer biology   chromosomes   gene expression   human   interleukin-1 signalling   mouse   telomere   telomeric repeat binding factor 2   triple-negative breast cancer   tumour immunity   tumour macrophages  

摘要： Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (telomeric repeat binding factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like and . Further, expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with expression. The use of both IL1 Receptor antagonist (IL1RA) and targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (>90 patients), tumour-derived organoids, cancer cells, and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.

关键词： COPD   IL13   SNP-SNP   stratified analyses   susceptibility  

摘要： BACKGROUND:Chronic obstructive pulmonary disease (COPD) is characterized by persistent respiratory symptoms and airflow limitation. Interleukin-13 (IL13), associated with T-helper type 2 cells, plays a crucial role in COPD pathophysiology. This study aimed to investigate the relationship of single nucleotide polymorphisms (SNPs) in IL13 to COPD risk. METHODS:Five candidate SNPs of IL13 were genotyped using MassARRAY iPLEX platform in a cohort of472 COPD patients and 472 healthy controls. Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Additionally, Multifactor dimensionality reduction (MDR) software was utilized to assess the combined impact of SNP-SNP interactions on COPD risk. RESULTS:IL13 rs20541 (OR: 1.24, p: 0.028), rs1295685 (OR: 1.31, p: 0.006), rs848 (OR: 1.27, p: 0.016), and rs847 (OR: 1.30, p: 0.007) were associated with COPD risk. Moreover, IL13 variants were related to the increased COPD risk in females, individuals aged ≥ 68 year, non-smokers or non-drinkers. The optimal multi-locus model was identified as the combination of rs20541 and rs1295685. CONCLUSION:Our findings indicated the association between IL13 variants and an elevated risk of developing COPD, especially rs1295685 and rs847. These findings could have implications for understanding the role of IL13 variants in COPD predisposition.

关键词： Human leukemia xenograft model   Immunodeficiency   Phenotype   SCID rat  

摘要： BACKGROUND:Genetically immunodeficient mice lacking Il2rg and Rag2 genes have been widely utilized in the field of biomedical research. However, immunodeficient rats, which offer the advantage of larger size, have not been as extensively used to date. Recently, Severe Combined Immunodeficiency (SCID) rats were generated using CRISPR/Cas9 system, targeting Il2rg and Rag2 in National BioResource Project in Japan. We imported and investigated more detailed phenotypes of wild-type (WT) Il2rg knockout (KO), Rag2 KO and Il2rg/Rag2 KO rats for 20 weeks. RESULTS:During experiments, Il2rg KO, Rag2 KO and Il2rg/Rag2 KO rats showed decreased white blood cells and systemic lymphopenia, with reduced CD4+, CD8+ T cells and CD161+ NK cells. Additionally, all KO strains exhibited reduced relative spleen weights, hypoplasia of the germinal center in the white pulp, and atrophy with the disappearance of the boundary between the cortex and medulla in the thymus, compared to WT rats. Furthermore, we established human acute lymphoblastic leukemia xenograft rat model by intravenously injecting 5.0 × 10 cells/kg of NALM6 cells into Il2rg/Rag2 KO rats. CONCLUSIONS:These findings indicate that Il2rg KO, Rag2 KO, and Il2rg/Rag2 KO rats exhibited SCID phenotypes, suggesting their potential application as immunodeficient animal models for tumor xenograft studies.

关键词： T cells   allergy   contact hypersensitivity   inflammatory skin diseases   transcription factors  

摘要： A plethora of data supports a major role of CD4 and CD8 T lymphocytes for the initiation, progression and maintenance of allergic contact dermatitis (ACD). However, in-depth understanding of the molecular mechanisms is still limited. NFATc1 plays an essential role in T cell activation. We therefore investigated its impact on contact hypersensitivity (CHS), the mouse model for ACD. The CHS response to 2,4,6-trinitrochlorobenzene (TNCB) was diminished in Nfatc1xCd4-cre mice (Nfatc1) as compared to wild-type (WT) animals and associated with a lower percentage of interleukin (IL) 17-producing CD8 T (Tc17) cells in both inflamed skin and draining lymph nodes (dLN). In vitro Tc17 polarization assays revealed that Nfatc1 CD8 T cells have a reduced capacity to polarize into Tc17 cells. Applying single-cell RNA sequencing, we realized that NFATc1 controls the T cell differentiation fate. In the absence of NFATc1, CD8 T cells favour the development of Interferon (IFN)-γ-secreting CD8 T (Tc1) lymphocytes while in its presence they turn into Tc17 cells. Finally, the adoptive transfer of TNCB-sensitized WT CD8 T cells restored the CHS response in naïve Nfatc1mice. Our data demonstrate that NFATc1 contributes to the development of Tc17 cells and might present a promising target to alleviate CD8 T cell-mediated allergic responses.

关键词： Atoh1   MHC II   Muc2   RV   pathogenesis   receptor   resistance   secretory cell   tropism  

摘要： Enteric pathogen rotavirus (RV) primarily infects mature enterocytes at the tips of the intestinal villi; however, the role of secretory Paneth and goblet cells in RV pathogenesis remains unappreciated. Atoh1 knockout mice (Atoh1cKO) were used to conditionally delete Paneth, goblet, and enteroendocrine cells in the epithelium to investigate the role of secretory cells in RV infection. Unexpectedly, the number of infected enterocytes and the amount of RV shedding in the stool were greatly decreased following secretory cell deletion. Resistance to RV infection persisted for 7 days after virus inoculation, and Atoh1 knockout mice co-housed with infected wild-type mice were uninfected, based on lack of shedding virus, despite the highly infectious nature of RV. This response was directly proportional to the extent of secretory cell deletion, with infection predominantly occurring in areas containing intact secretory cells. RV infection of knockout mice recapitulated the secretory cell deletion phenotype, indicating that goblet cell loss is responsible for attenuated infection. Transcriptome analysis of Atoh1cKO intestine via single-cell RNA sequencing revealed downregulation of MHC II molecules specifically in tip enterocytes, and MHC II mice were likewise resistant to RV infection. These data suggest a previously unknown role for both MUC2 and MHC II expression in susceptibility to RV *** (RV) is a highly contagious pathogen that primarily infects mature intestinal enterocytes. Murine rotavirus readily infects infant and adult mice, enabling evaluation of RV infection and immunity. We report that mice lacking secretory cells are one of the few genetically modified mouse lines not susceptible to murine rotavirus. Further investigation revealed loss of mucin 2 (MUC2) expression or major histocompatibility complex II (MCH II) expression recapitulated this rare resistance to rotavirus infection, suggesting a previously unrecognized link between s

关键词： Apigenin   Apoptosis   Jie-Geng-Tang   TNF-α pathway  

摘要： Jie-Geng-Tang (JGT), composed of Platycodon grandiflorus (Jacq.) A. DC and Glycyrrhiza uralensis Fisch, is widely used in traditional Chinese medicine for its potential effects in preventing pulmonary fibrosis (PF). This study systematically explored the effects of JGT's water and 70% EtOH extracts in bleomycin (BLM)-induced PF models. In vitro, the 70% EtOH extract significantly reversed BLM-induced reductions in cell viability and apoptosis, whereas the water extract had limited impact. In vivo, the EtOH extract markedly reduced fibrosis markers, such as α-SMA and collagen-I, alleviating lung tissue damage and collagen deposition. UPLC-Q-TOF/MS analysis revealed that the EtOH extract contained a higher abundance of flavonoids compared to the water extract. Through network pharmacology analysis of the EtOH extract, four key flavonoids-apigenin, kaempferol, kaempferol 3-glucuronoside, and quercetin-were identified as crucial compounds. These flavonoids were found to reverse BLM-induced cell viability loss, with apigenin showing the most pronounced effect by modulating the TNF-α signaling pathway and inhibiting caspase-3 activation. Apigenin, as a primary active component derived from JGT, holds significant potential as a preventive agent against pulmonary fibrosis.

关键词： NLRP3 inflammasome   aortic fibrosis   heart failure with preserved ejection fraction   left ventricular diastolic dysfunction   macrophage  

摘要： Fibrosis is the main pathological feature of aortic stiffness, which is a common extracardiac comorbidity of heart failure with preserved ejection fraction (HFpEF) and a contributor to left ventricular (LV) diastolic dysfunction. Systemic low-grade inflammation plays a crucial role in the pathogenesis of HFpEF and the development of vascular fibrosis. In this study, we investigate the inflammatory mechanism of aortic fibrosis in HFpEF using a novel mouse model. LV diastolic dysfunction with preserved ejection fraction and aortic fibrosis induced by a high-fat diet (HFD) combined with subcutaneous aldosterone infusion are utilized. The constructed model exhibits augmented macrophage recruitment and NLR family pyrin domain containing 3 (NLRP3)-dependent interleukin (IL)-1β production in fibrotic aortas. In addition, a bone marrow transplant is employed to induce macrophage-specific NLRP3 deficiency in the HFpEF mouse model. These mice show almost completely suppressed cleaved-caspase-1 and mature IL-1β protein expression in the aortas, indicating that macrophage NLRP3 inflammasome activation enhances the IL-1β overproduction in fibrotic aortas. Furthermore, we show that macrophage NLRP3 inflammasome inhibition improves aortic fibrosis and LV diastolic dysfunction. In conclusion, this study demonstrates the pivotal effect of macrophage NLRP3-dependent IL-1β production on aortic fibrosis and cardiac function in HFpEF, suggesting a potential target for HFpEF therapy.

关键词： ankylosing spondylitis   gut microbiota   inflammation   immune system dysregulation   microbial diversity   TNF inhibitors  

摘要： Objective This study aims to evaluate the impact of tumor necrosis factor (TNF) inhibitors on the gut microbiota in patients with ankylosing spondylitis (AS) and investigate the potential therapeutic benefits of microbial modulation. Given the role of gut microbiota in immune regulation and its association with autoimmune conditions like AS, this research seeks to identify microbial targets that could enhance treatment outcomes.

关键词： Lymphoproliferation   T lymphocytes   cytokines   disease activity   organochlorine pesticides  

摘要： BACKGROUND:One of the common findings in systemic sclerosis (SSc) patients has been long-term exposure to environmental toxins such as pesticides. However, the data available shows an equivocal association between pesticide exposure and autoimmunity in SSc. METHODS:We investigated the levels of organochlorine pesticides (OCPs) in blood of 20 SSc patients and 17 healthy controls, and also studied their effect on T lymphocytes and their functional responses. RESULTS:We found higher levels of hexachlorocyclohexane (HCH- α-, β-, and γ) and o,p'-dichlorodiphenyltrichloroethane (DDT) metabolite (p,p΄-DDE) in blood of SSc patients. treatment of SSc patient PBMCs with either of HCH (100 mM) or DDT (50 µM) caused a significant increase merely in CD8 memory (CD8CD45RO) T lymphocytes. We also observed reduced FoxP3 expression in CD4CD25 (regulatory T cells) of SSc patients. Neither HCH nor DDT exposure of SSc PBMCs altered significantly the secretion of IL-2, IL-10, or IFN-γ, but both of these pesticides elevated their IL-4 (a pro-fibrotic cytokine) secretion. CONCLUSION:Taken together, our findings indicate that persistent exposure to these OCPs results in decreased lymphoproliferative activity which promotes disease activity by producing pro-fibrotic cytokine(s). Thus, SSc patients are less able to initiate or augment an immune response to foreign antigens, when there is substantial suppression of lymphocyte function, which increases their susceptibility to infection. Strategies to prevent and control pesticide exposure may play an important role in reducing the morbidity and mortality associated with this disease.

摘要： Inhibitory killer cell immunoglobulin-like receptors (iKIRs) are a family of inhibitory receptors that are expressed by natural killer (NK) cells and late-stage differentiated T cells. There is accumulating evidence that iKIRs regulate T cell-mediated immunity. Recently, we reported that T cell-mediated control was enhanced by iKIRs in chronic viral infections. We hypothesized that in the context of autoimmunity, where an enhanced T cell response might be considered detrimental, iKIRs would have an opposite effect. We studied Type 1 diabetes (T1D) as a paradigmatic example of autoimmunity. In T1D, variation in the Human Leucocyte Antigen (HLA) genes explains up to 50% of the genetic risk, indicating that T cells have a major role in T1D etiopathogenesis. To investigate if iKIRs affect this T cell response we asked whether HLA associations were modified by iKIR genes. We conducted an immunogenetic analysis of a case-control T1D dataset (N = 11,961) and found that iKIR genes, in the presence of genes encoding their ligands, have a consistent and significant effect on protective HLA class II genetic associations. Our results were validated in an independent data set. We conclude that iKIRs significantly decrease HLA class II protective associations and suggest that iKIRs regulate CD4+ T cell responses in T1D.