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关键词： enterochromaffin cells   IL-18 receptor   intestinal injury   revival stem cells   inflammasomes  

摘要： Upon injury, epithelial-derived IL-18 is released and induces an inflammatory response in underlying IL18R1+ lamina propria cells. Notably, Il18r1 is also predicted to be expressed and functional in intestinal epithelial cells (IECs), since epithelial IL18R1 deficiency contributes to worsened outcomes upon inflammatory challenge. However, the nature of Il18r1+ IECs, and their subsequent role in epithelial-intrinsic IL-18 signaling is poorly characterized. Here, we show that, in the murine small intestine, the IL-18 receptor is expressed by rare IECs that we identified to be a subset of enterochromaffin cells (ECC). While these cells are the major producers of serotonin in the intestine, we found no evidence that IL-18 regulated serotonin metabolism or release. Rather, upon radiation-induced injury, Il18r1+ cells appeared in the crypt base and took on a revival stem cell (revSC) program, marked by mixed expression of YAP/TAZ and enteroendocrine genes signatures. Functionally, irradiated Il18-/- mice display reduced epithelial proliferation and altered differentiation in the small intestine, characterized by increased Paneth cells (PC) and elevated Wnt3 levels, which was partially recapitulated in Il18-/- ileal organoids. In sum, we identified an Il18r1+ population in the epithelium and revealed a role for IEC-intrinsic IL-18 signaling during injury.

关键词： CD1d   iNKT细胞   α-半乳糖酰神经酰胺   细胞因子  

摘要： 目的 检测多种肿瘤细胞系的CD1d表达情况,探讨iNKT细胞对不同肿瘤细胞系杀伤的敏感性。方法 将培养的多种肿瘤细胞系制备成单细胞悬液,使用CD1d抗体与肿瘤细胞共孵育,通过流式细胞术检测CD1d在各种肿瘤细胞系中的表达;将iNKT细胞与肿瘤细胞按照效靶比E∶T=10∶1、5∶1和1∶1共孵育,RTCA esight成像检测法监测iNKT细胞对肿瘤细胞杀伤情况,通过流式细胞术检测iNKT细胞表面分子的表达,通过ELISA检测iNKT细胞激活后的细胞因子分泌。结果 在Jurkat、Jeko-1、U2OS、A375、Hep-3B细胞系均可检测到CD1d表达,其阳性比例分别为98.40%、93.80%、67.10%、43.80%、11.00%;而肿瘤细胞系Huh7、OVCAR3、MKN45、AGS、H460、MKN7、MDA-MB-453为CD1d阴性。激活的iNKT细胞表达NK细胞激活受体CD226、NKG2D,同时能够迅速分泌大量的细胞因子和细胞毒性分子如IFNγ和Granzyme B等。iNKT细胞对CD1d阳性细胞(除Jeko-1细胞)以及CD1d阴性的肿瘤细胞系的广泛杀伤能力,并在高效靶比时,对肿瘤细胞的杀伤效率最强。当在实验体系中额外添加外源性脂质α-Galcer时,原本对Jeko-1细胞不具备杀伤效应的iNKT细胞重新获得杀伤能力,也能增强iNKT细胞对A375细胞的杀伤。结论 iNKT细胞显示出对CD1d阳性(除Jeko-1细胞)及阴性肿瘤细胞系具有广泛杀伤能力,且在高效靶比时杀伤效果最强;α-Galcer可增强iNKT细胞对CD1d阳性肿瘤细胞系的杀伤能力。

关键词： cutaneous leishmaniasis   Leishmania   Staphylococcus aureus   skin infection   microbiota  

摘要： Cutaneous leishmaniasis is a parasitic infection that causes a spectrum of pathology ranging from single, self-healing lesions to disfiguring chronic wounds. In severe disease, uncontrolled inflammation exacerbates tissue damage and delays healing, though the contributing factors are unclear. We previously observed that delayed healing was associated with Staphylococcus aureus in the lesional microbiota of patients with cutaneous leishmaniasis. To investigate how S. aureus impacts immunopathology during leishmania infection, we established a murine model of S. aureus colonization with clinical isolates followed by Leishmania infection. S. aureus triggered early production of interleukin (IL)-1 beta during Leishmania infection, which was critical for neutrophil recruitment and cutaneous inflammation. S. aureus isolates differentially induced IL-1 beta and neutrophil recruitment, and isolates that induced greater neutrophil recruitment were resistant to neutrophil killing and persisted longer. We reveal a mechanism whereby S. aureus mediates immunopathology during cutaneous leishmaniasis, suggesting IL-1 beta as a promising immunomodulatory target for non-healing infections.

关键词： ILC3s   Inflammatory cytokines   Intestinal barrier   MSI2   Ulcerative colitis  

摘要： Background: Ulcerative colitis (UC) is an inflammatory bowel disease with an unknown cause. Previous studies have shown that Group 3 innate lymphoid cells (ILC3s) are crucial for maintaining intestinal mucosal immune homeostasis by producing key cytokines such as IL-22 and IL-17 A. While the RNA-binding protein Musashi-2 (MSI2) is recognized as essential for promoting intestinal epithelial regeneration post-injury, its impact on immune regulation remains unclear. Therefore, we aim to investigate the protective mechanisms associated with ILC3s-specific MSI2 deletion in a mouse model of ulcerative colitis. Methods: Dextran sulfate sodium (DSS) was used to induce a mouse colitis model. Colitis severity was evaluated through weight loss, diarrhea, fecal traits, colon length, and pathological scoring. Transcriptome sequencing was utilized to identify differentially expressed genes in colon tissues. Flow cytometry was employed to measure the quantity and functionality of ILC3s. Western blot was conducted to analyze protein expression, while real-time polymerase chain reaction and enzyme-linked immunosorbent assay were employed to quantify inflammatory factors. Additionally, immunofluorescence, AB-PAS staining, and immunohistochemistry were employed to evaluate the integrity of the intestinal barrier. Results: Following DSS treatment, colon damage was milder in Msi2 Delta Rorc mice than in Msi2fl/flmice. Transcriptomic analysis revealed the down-regulation of cytokines and pro-inflammatory factors in the colon tissue of Msi2 Delta Rorc mice. Flow cytometry showed that specific deletion of MSI2 reduced the infiltration of ILC3s in the intestinal lamina propria of Msi2 Delta Rorc mice and decreased IL-17 A production. The reduction of IL-17 A-mediated immune responses lessened inflammatory damage to the intestinal barrier, thereby reducing colitis severity. Conclusions: Specific deletion of MSI2 alleviates DSS-induced colitis in mice by reducing ILC3s infiltration and IL-17

关键词： HLA   Streptococcus mutans   Saliva   Caries   Genetics   DRB1*0401  

摘要： Background Genetic factors significantly influence caries development and the colonization of oral bacteria, which could explain why some individuals are more prone or resistant to caries. Human leukocyte antigen (HLA) class II is a component in the adaptive immune system that has been associated with the colonization of oral bacteria such as Streptococcus mutans. This study aimed to investigate the association between specific alleles and genotypes of HLA-DRB1 on subgroup level and the colonization of S. mutans in a group of Swedish children. Methods Blood samples from 357 children were analyzed for HLA using next generation sequencing. Saliva samples were collected and analyzed for S. mutans, after which the subjects were divided into three groups: low, moderate, and high levels of colony forming units (CFU). The frequency of DRB1 alleles and genotypes was compared between the three groups. In addition, colonization levels, including the extremely high and low S. mutans CFU in individuals with alleles DRB1*0401, *0404, and *0301 were compared to the rest of the material. Results Individuals with DRB1*0401 were significantly associated with the extremely high CFU levels, since CFU levels > 100 were observed in 4.3% of individuals with DRB1*0401, compared to none among those without the allele (p = 0.009, Fisher's exact test). No statistical association was noted between the low, moderate, and high S. mutans groups and specific alleles or genotypes. Conclusions The findings suggest a potential relation between HLA class II alleles and the colonization of S. mutans. Specifically, carrying the DRB1*0401 allele may be a predisposing factor for higher levels of colonization.

关键词： 苦参   肿瘤   免疫微环境   免疫细胞   细胞因子   炎症因子  

摘要： 近年来，对肿瘤免疫微环境的研究逐渐成为关注热点。肿瘤免疫微环境是一个复杂的系统，可通过对微环境中肿瘤细胞、免疫细胞、炎症因子等成分进行调节，有效控制肿瘤的生长和转移。苦参是一种药用植物，主要成分为生物碱及黄酮类化合物，具有抗炎、抗菌、抗病毒、抗肿瘤以及免疫调节作用，能作用于肿瘤免疫微环境中免疫细胞、细胞因子、炎症因子等，可通过抑制肿瘤细胞增殖、侵袭和转移、干扰细胞周期、调节肿瘤代谢重编程以及抑制血管生成等发挥抗肿瘤作用。苦参对肿瘤免疫微环境的调节作用为肿瘤的临床治疗提供了新的策略。本文对苦参的生物学特性、抗肿瘤作用和作用机制及其对肿瘤免疫微环境的调节作用进行综述。

关键词： regulatory T cells   Foxp3   type 1 responses   GM-CSF   Treg suppressor function   IL-2   tissue-invading phagocytes   inflammation  

摘要： Regulatory T (T-reg) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. T-reg cell depletion or dysfunction results in fatal multiorgan inflammation linked to unrestrained effector T cell expansion. Here, we combine in vivo gene targeting and fate-mapping with high-dimensional cytometry to identify T-reg cells' steady-state function and suppressive mechanisms that prevent autoimmune inflammation and dissect the T helper (T-H) cell-derived cytokines and responding cells executing tissue damage upon global loss of peripheral tolerance. We unveil that type 1 cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)gamma, but not interleukin (IL)-17A, direct the ensuing immunopathology and mortality. GM-CSF orchestrates tissue invasion by monocytes and granulocytes and enhances their reactive oxygen species production and phagocytic capability. IL-2 modulation by T-reg cells is crucial in restraining pathogenic GM-CSF-producing T-H cells. Our study highlights the critical role of T-reg cells and IL-2 signaling in controlling GM-CSF-producing T-H cells and type 1 responses to curb phagocyte-mediated tissue destruction.

关键词： 番茄环纹斑点病毒   RdRP   原核表达   多克隆抗体  

摘要： 番茄环纹斑点病毒（Tomato zonate spot virus,TZSV）的依赖RNA的RNA聚合酶（RNA-dependent RNA polymerase,RdRP）是病毒复制和转录的核心酶。本研究通过原核表达RdRP的部分片段并制备多克隆抗体，旨在为TZSV的检测和诊断提供关键材料，并为后续研究RdRP在病毒基因表达调控以及病毒与宿主互作等方面的作用奠定基础。结果表明：从TZSV染病番茄中扩增出大小为903 bp的TZSV RdRP-a片段，原核表达获得大小为36 kDa的重组蛋白；蛋白纯化后免疫小鼠，制备多克隆抗体，获得的多抗血清效价可达到1∶128 000；经Western blot鉴定，所制备的多克隆抗体能够特异性识别TZSV-RdRP重组蛋白和天然TZSV。

关键词： Serpin A3   TNF-alpha   Retinoic acid   Vitamin B6   In vitro adipogenesis  

摘要： SERPINA3G participates in the antiadipogenesis and insulin resistance induced by TNF-alpha in 3T3-F442A murine cells. Here, we show that the human orthologue SERPINA3 is expressed in human subcutaneous and visceral adipose depots of normal-weight individuals and that TNF-alpha and RA induced the overexpression of SERPINA3 mRNA in cultured human subcutaneous and visceral adipocytes, although only TNF-alpha induced the expression of serpin A3 protein. We also demonstrate that vitamin B6 abrogated the expression of the SERPINA3 gene and diminished the anti-adipogenic effects of TNF-alpha on mature adipocytes. Our results indicate that SERPINA3 is expressed in human adipose tissues and modulates the antiadipogenic effects of TNF-alpha, and suggest serpin A3 could be a promissory target in the inflammatory processes linked to obesity and other adipose dysfunctions.

关键词： Epstein-Barr virus-associated NK-cell lympho-proliferative diseases   Long non-coding RNA   LINC02446   Hemophagocytic lymphohistiocytosis   IL-10   KLRs  

摘要： Introduction: Refractory Epstein-Barr virus-associated NK-cell lymphoproliferative diseases (EBV-NK-LPDs) are prone to hemophagocytic lymphohistiocytosis (HLH) with short survival and poor prognosis. Although various therapies have been used to relieve the symptoms, hematopoietic stem cell transplantation is considered the only potentially therapeutic approach. There is an urgent need to explore the pathogenesis of EBV-NK-LPDs and develop an effective better treatment. Methods: Here, we investigated long non-coding RNA (lncRNA) profile using high-throughput RNA sequencing data (n = 6, healthy donors;n = 5, infectious mononucleosis;n = 10, chronic active Epstein-Barr virus disease (CAEBV)-NK;n = 7, CAEBV-T) and screened out LINC02446, whose upregulation was further validated by quantitative real-time polymerase chain reaction in EBV-NK-LPDs. We further explored the correlation between LINC02446 and the clinical characteristics of patients with EBV-NK-LPDs. Then, based on sequencing data, we performed in vitro experiments to investigate the function and mechanism of LINC02446 in EBV-NK-LPDs. Results: LINC02446 was specifically highly expressed in NK cells of EBV-NK-LPDs patients. EBV-NK-LPDs patients with high expression of LINC02446 showed higher EBV-DNA copy number and ferritin levels, as well as a higher incidence of HLH. LINC02446 was closely related to the KLRs family and LINC02446 could regulate the expression of KLRs genes. In addition, LINC02446 positively regulated the expression of IL-10 in EBV-NK-LPDs cell lines, which revealed that LINC02446 may promote HLH by upregulating IL-10 in EBV-NK-LPDs. Conclusions: This is the first study that LINC02446 regulates the expression of KLRs family and IL-10 in EBV-NKLPDs, resulting in lymphoma progression and HLH occurrence, showing its potential as a therapeutic target for EBV-NK-LPDs.