Cellular immunology最新文献_第4页

ANAPC5 mitigates acute lung injury through regulating macrophage M1/M2 polarization via the EGFR/CD24 axis ANAPC5通过EGFR/CD24轴调控巨噬细胞M1/M2极化，减轻急性肺损伤

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-08-08 DOI: 10.1016/j.cellimm.2025.105013

Yiqi Wang , Xiuhua Zhang , Jiannan Zhang , Mingbo Zhao, Yang Chong, Quankuan Gu, Xianglin Meng, Mingyan Zhao

Acute lung injury (ALI) is a respiratory disease induced by uncontrolled inflammatory responses in the lungs. The pathological features of ALI include alveolar structural damage and pulmonary edema, which ultimately leads to pulmonary dysfunction. ANAPC5 (Anaphase-promoting complex subunit 5) is an E3 ubiquitin ligase known for its anti-inflammatory properties. This study aims to investigate the effects of ANAPC5 on ALI and its underlying molecular mechanism. In the lung tissue of an ALI mouse model induced by lipopolysaccharide (LPS) administration, we observed downregulation of ANAPC5. Through both in vivo and in vitro experiments, we assessed the effect of ANAPC5 on lung injury by conducting pathological analysis and molecular biological detection. ANAPC5 overexpression alleviated inflammatory cell infiltration, reduced alveolar wall thickening, suppressed pulmonary inflammation, and decreased the levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue of the ALI model. Moreover, ANAPC5 inhibited M1 polarization and promoted M2 polarization of macrophages both in vitro and in vivo. We also found that ANAPC5 significantly suppressed the activation and expression of the epidermal growth factor receptor (EGFR) through inducing its ubiquitination in macrophages. In LPS-induced M1 macrophages, the presence of EGFR significantly decreased CD24 expression, followed by reversing the inhibitory effects of ANAPC5 on inflammatory responses and macrophage polarization. Collectively, our findings suggest that ANAPC5 serves as a therapeutic molecular target that mitigates ALI through regulating macrophage M1/M2 polarization via the EGFR/CD24 axis.

急性肺损伤（ALI）是一种由肺部不受控制的炎症反应引起的呼吸系统疾病。ALI的病理特征包括肺泡结构损伤和肺水肿，最终导致肺功能障碍。ANAPC5（后期促进复合体亚基5）是一种E3泛素连接酶，以其抗炎特性而闻名。本研究旨在探讨ANAPC5在ALI中的作用及其潜在的分子机制。在脂多糖（LPS）诱导的ALI小鼠模型肺组织中，我们观察到ANAPC5的下调。通过体内和体外实验，我们通过病理分析和分子生物学检测来评估ANAPC5对肺损伤的作用。ANAPC5过表达可减轻ALI模型炎症细胞浸润，减轻肺泡壁增厚，抑制肺部炎症，降低支气管肺泡灌洗液（BALF）和肺组织中炎症因子水平。此外，ANAPC5在体外和体内均能抑制巨噬细胞的M1极化，促进M2极化。我们还发现ANAPC5通过诱导巨噬细胞中表皮生长因子受体（EGFR）的泛素化，显著抑制其激活和表达。在lps诱导的M1巨噬细胞中，EGFR的存在显著降低CD24的表达，随后逆转ANAPC5对炎症反应和巨噬细胞极化的抑制作用。总的来说，我们的研究结果表明ANAPC5作为一种治疗性分子靶点，通过EGFR/CD24轴调节巨噬细胞M1/M2极化来减轻ALI。

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引用次数: 0

Chloroquine treatment ameliorates experimental autoimmune encephalomyelitis by inhibiting T cell differentiation and pDC accumulation 氯喹治疗通过抑制T细胞分化和pDC积累改善实验性自身免疫性脑脊髓炎

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-07-17 DOI: 10.1016/j.cellimm.2025.105010

Yonghai Li , Yue Shao , Xianfen Ma , Yaning Li , Yijia Yang , Fengyuan Wang , Yushan Yan , Xiaoxi Hu , Yujie Dai , Meng Li , Max Löhning , Ping Shen , Juntang Lin

Objectives

Chloroquine (CQ) has been used to treat rheumatoid arthritis and systemic lupus erythematosus, but its use in multiple sclerosis (MS) is limited by side effects and insufficient efficacy. To enhance treatment outcomes, understanding CQ's therapeutic mechanisms in MS is crucial. Thus, we administered CQ to mice with experimental autoimmune encephalomyelitis (EAE) and investigated its disease-ameliorating effects and underlying cellular mechanisms.

Methods

CQ was applied intraperitoneally six days after EAE induction, immune responses, with a focus on inflammatory and regulatory T cells, as well as dendritic cells in blood, lymph nodes, spleen, and bone marrow were analyzed by flow cytometry.

Results

CQ treatment significantly reduced cumulative disease score and maximal disease score in CQ-treated group. Immunohistochemical analysis of the spinal cords confirmed the reduced demyelination after CQ treatment, which is accompanied by significantly decreased infiltration of T cells, B cells, and macrophages, and less activated microglia cells. Flow cytometry analysis of peripheral lymphoid organs revealed a significant decrease of inflammatory Th17 cells, which is associated with reduced pDC and their IFN-α expression, as well as Treg cells in CQ-treated mice. Indeed, depletion of pDC alone or simultaneously with CQ treatment significantly reduced EAE severity.

Conclusion

Our results demonstrated that CQ treatment inhibits the development of EAE disease on one hand by enhancing the expansion of Treg in dLN and spleen, and on the other hand by inhibiting the accumulation of pDC and their IFN-α expression in the spleen and bone marrow. This joint effort restricts the level of inflammation in peripheral and later in CNS. Furthermore, developing a pDC-targeted CQ treatment will not only increase the treatment efficiency, but also largely decrease side effects.

目的氯喹（chloroquine， CQ）已被用于治疗类风湿性关节炎和系统性红斑狼疮，但其在多发性硬化症（multiple sclerosis， MS）中的应用受到副作用和疗效不足的限制。为了提高治疗效果，了解CQ在多发性硬化症中的治疗机制至关重要。因此，我们将CQ给予实验性自身免疫性脑脊髓炎（EAE）小鼠，并研究其疾病改善作用和潜在的细胞机制。方法在EAE诱导后第6天腹腔注射scq，流式细胞术分析各组小鼠的免疫反应，重点观察炎症和调节性T细胞，以及血液、淋巴结、脾脏和骨髓中的树突状细胞。结果cq治疗组累积疾病评分和最大疾病评分显著降低。脊髓免疫组化分析证实，CQ治疗后脊髓脱髓鞘减少，T细胞、B细胞、巨噬细胞浸润明显减少，活化小胶质细胞减少。外周淋巴器官的流式细胞术分析显示，cq处理小鼠炎症性Th17细胞和Treg细胞显著减少，这与pDC及其IFN-α表达减少有关。的确，单独使用pDC或同时使用CQ治疗可显著降低EAE的严重程度。结论CQ治疗一方面通过增强dLN和脾脏中Treg的扩增，另一方面通过抑制脾脏和骨髓中pDC的积累及其IFN-α的表达来抑制EAE疾病的发展。这种共同的努力限制了外周和中枢神经系统的炎症水平。此外，开发针对pdc的CQ治疗方法不仅可以提高治疗效率，还可以大大减少副作用。

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引用次数: 0

Enhancing the antitumor activity of CD19/BCMA CAR-T cells in vitro with a PD1IL7R chimeric switch receptor PD1IL7R嵌合开关受体在体外增强CD19/BCMA CAR-T细胞的抗肿瘤活性

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-07-14 DOI: 10.1016/j.cellimm.2025.105001

Kai Yan, Zhongdang Xiao

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its long-term efficacy is hindered by antigen escape, T-cell exhaustion, and the immunosuppressive tumor microenvironment (TME). Programmed death ligand 1 (PD-L1) expression in the TME inhibits CAR-T cell function, limiting persistence and cytotoxic capacity. To address this, we engineered CD19/BCMA-targeted CAR-T cells co-expressing a PD1IL7R chimeric switch receptor (CSR). This novel receptor converts PD-L1-mediated inhibitory signals into IL7R-driven pro-survival and proliferative pathways, enhancing CAR-T cell expansion, persistence, and cytotoxicity in a PD-L1–dependent but antigen-specific manner. In vitro, CD19/BCMA-PD1IL7R CAR-T cells exhibit improved central memory T-cell formation, increased cytokine secretion, and superior antitumor activity compared to conventional CAR-T cells. Notably, these functional enhancements were evident even at low levels of PD-L1 expression on target cells, and no off-target effects were observed. Our findings suggest that incorporating the PD1-IL7R switch receptor into CAR-T cells effectively overcomes PD-L1–mediated immunosuppression, enhancing both their persistence and antitumor efficacy. This approach offers a versatile strategy for improving CAR-T therapy in the treatment of both hematologic and solid tumors.

嵌合抗原受体(CAR)-T细胞疗法已经彻底改变了血液系统恶性肿瘤的治疗，但其长期疗效受到抗原逃逸、t细胞耗竭和免疫抑制肿瘤微环境（TME）的阻碍。程序性死亡配体1 （PD-L1）在TME中的表达抑制CAR-T细胞功能，限制持久性和细胞毒性能力。为了解决这个问题，我们设计了CD19/ bcma靶向CAR-T细胞，共表达PD1IL7R嵌合开关受体（CSR）。这种新型受体将pd - l1介导的抑制信号转化为il7r驱动的促生存和增殖途径，以pd - l1依赖但抗原特异性的方式增强CAR-T细胞的扩增、持久性和细胞毒性。在体外，与常规CAR-T细胞相比，CD19/BCMA-PD1IL7R CAR-T细胞表现出改善的中枢记忆t细胞形成、增加的细胞因子分泌和优越的抗肿瘤活性。值得注意的是，即使靶细胞上的PD-L1表达水平较低，这些功能增强也很明显，并且没有观察到脱靶效应。我们的研究结果表明，将PD1-IL7R开关受体纳入CAR-T细胞有效地克服了pd - l1介导的免疫抑制，增强了它们的持久性和抗肿瘤功效。这种方法为改善CAR-T治疗血液和实体肿瘤提供了一种通用的策略。

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引用次数: 0

Identification of Epstein-Barr virus nuclear antigen 1 (EBNA1)-specific T-cell receptors: implications for immunotherapy targeting EBV-associated malignancies eb病毒核抗原1 （EBNA1）特异性t细胞受体的鉴定：对ebv相关恶性肿瘤免疫治疗的意义

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-07-11 DOI: 10.1016/j.cellimm.2025.105002

Ying Liu , Yaqi Pan , Huirong Ding , Wei He , Huanyu Chen , Zhe Hu , Zheming Lu , Yang Ke

Background

Epstein-Barr virus nuclear antigen (EBNA1) is uniquely expressed across all three EBV latency types, making it an ideal target for TCR-engineered T-cell therapy against EBV-associated malignancies. However, preparation of EBNA1-specific TCR-T cells, particularly for EBV latency I type, remains exploratory.

Methods

EBNA1-specific T cells were stimulated using autologous dendritic cells (DCs) pulsed with peptides synthesized from the complete sequence (except the glycine-alanine repeat region) of the EBNA1 of EBV strain B95–8. For pre-stimulated and post-stimulated T cells, candidate EBNA1-specific TCRs with significantly increased frequencies were identified using high-throughput single-cell TCR V(D) J sequencing. The functionality of EBNA1-specific TCR-engineered T cells was assessed in vitro against lymphoblastoid cell lines (LCLs) and EBNA1 peptide-pulsed DCs.

Results

EBNA1-specific T cells were successfully expanded. Candidate EBNA1-specific TCRs were isolated, corresponding TCR gene sequences were constructed and introduced into peripheral blood T cells. Engineered T cells expressing EBNA1-specific TCR demonstrated specific recognition of EBNA1 presented by autologous LCLs and DCs in vitro.

Conclusions

This study establishes the feasibility of expanding functional EBNA1-specific TCR-T cells, providing a foundation for adoptive cell therapy targeting all EBV-associated malignancies, including latency I.

depstein - barr病毒核抗原（EBNA1）在所有三种EBV潜伏期类型中都有独特的表达，使其成为tcr工程t细胞治疗EBV相关恶性肿瘤的理想靶点。然而，ebna1特异性TCR-T细胞的制备，特别是EBV潜伏期I型，仍处于探索性阶段。方法采用以EBV菌株B95-8 EBNA1的完整序列（甘氨酸-丙氨酸重复区除外）合成的肽脉冲的自体树突状细胞刺激sebna1特异性T细胞。对于预刺激和后刺激的T细胞，使用高通量单细胞TCR V(D) J测序鉴定出频率显著增加的候选ebna1特异性TCR。EBNA1特异性tcr工程T细胞在体外对淋巴母细胞样细胞系（LCLs）和EBNA1肽脉冲dc的功能进行了评估。结果成功扩增bna1特异性T细胞。分离候选ebna1特异性TCR，构建相应的TCR基因序列并导入外周血T细胞。表达EBNA1特异性TCR的工程T细胞在体外表现出对自体lcl和dc特异性识别EBNA1的能力。结论本研究建立了扩增ebna1特异性功能TCR-T细胞的可行性，为针对所有ebv相关恶性肿瘤（包括潜伏期I）的过继细胞治疗提供了基础。

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引用次数: 0

Sfrp2-deficient colonic fibroblasts drive mucosal inflammation and epithelial injury in ulcerative colitis 在溃疡性结肠炎中，缺乏strp2的结肠成纤维细胞驱动粘膜炎症和上皮损伤

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-07-11 DOI: 10.1016/j.cellimm.2025.105003

Mengyuan Zhu , Zhanqiu Diao , Lei Hu , Zhipeng Fan

Ulcerative colitis (UC) is a chronic inflammatory disorder targeting the colon, which remains clinically challenging due to limited targeted therapies. Although intestinal fibroblasts have emerged as critical regulators of mucosal immunity and tissue repair, their molecular mechanisms in UC pathogenesis are poorly defined. Here, we investigate the functional role of secreted frizzled-related protein 2 (SFRP2, a Wnt signaling modulator) knockdown fibroblasts in immune homeostasis and the severity of UC using Sfrp2^flox/flox; Col1a2-Cre mice (fibroblast-specific knockout). In the dextran sulfate sodium (DSS)-induced colitis model, we found SFRP2 in fibroblasts have negative correlation with the severity of UC. That Sfrp2^Col1a2 CKO mice exhibited exacerbated colitis symptoms and accelerated inflammatory progression, and showed increased ratio of Th17 cells and decreased ratio of Treg cells. These findings revealed that Sfrp2 in fibroblasts plays a crucial role in protecting against inflammatory responses and T-cell immune dysregulation. Therefore, Sfrp2 may serve as a potential therapeutic target for UC treatment.

溃疡性结肠炎（UC）是一种以结肠为靶点的慢性炎症性疾病，由于靶向治疗有限，在临床上仍然具有挑战性。虽然肠成纤维细胞已成为粘膜免疫和组织修复的关键调节因子，但其在UC发病机制中的分子机制尚不明确。在这里，我们使用Sfrp2flox/flox研究了分泌卷曲相关蛋白2 （SFRP2，一种Wnt信号调节剂）敲低成纤维细胞在免疫稳态和UC严重程度中的功能作用；Col1a2-Cre小鼠（纤维母细胞特异性敲除）。在葡聚糖硫酸钠（DSS）诱导的结肠炎模型中，我们发现成纤维细胞中SFRP2与UC的严重程度呈负相关。Sfrp2Col1a2 CKO小鼠结肠炎症状加重，炎症进展加快，Th17细胞比例升高，Treg细胞比例降低。这些发现表明，成纤维细胞中的strp2在防止炎症反应和t细胞免疫失调中起着至关重要的作用。因此，strp2可能作为UC治疗的潜在治疗靶点。

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引用次数: 0

Acetyl-CoA subcellular compartmentalization regulates T cell adaptation 乙酰辅酶a亚细胞区隔化调节T细胞适应

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-06-28 DOI: 10.1016/j.cellimm.2025.105000

Annefien Tiggeler , Paul J. Coffer

Upon activation, naïve T cells undergo rapid proliferation and differentiation, giving rise to clonally expanded populations specifically tailored for an effective immune response. To meet the heightened bioenergetic and biosynthetic demands associated with activation, T cells adapt and reprogram both their metabolism and transcriptome. Beyond this, T cells are also able to dynamically adapt to fluctuations in the microenvironmental nutrient levels. While the adaptability of T cells is a well-established hallmark of their functionality, the molecular mechanisms by which metabolic responses underpin this flexibility remain incompletely defined. Acetyl-CoA, with its role as a central metabolite in mitochondrial ATP production, and a substrate for nuclear histone acetylation reactions, emerges as a key player in a metabolic-epigenetic axis. Recent evidence indicates that enzymes responsible for generating acetyl-CoA can translocate to the nucleus, supporting sub-cellular local acetyl-CoA production. Here, we explore the impact of acetyl-CoA metabolism on T cell functionality within different subcellular compartments and highlight the potential for intervention in acetyl-CoA metabolic pathways in T cell-driven autoimmune diseases and cancers.

激活后，naïve T细胞经历快速增殖和分化，产生专门为有效免疫反应量身定制的克隆扩增群体。为了满足与激活相关的更高的生物能量和生物合成需求，T细胞适应并重新编程其代谢和转录组。除此之外，T细胞还能够动态适应微环境营养水平的波动。虽然T细胞的适应性是其功能的一个公认的标志，但代谢反应支撑这种灵活性的分子机制仍然不完全确定。乙酰辅酶a作为线粒体ATP生成的中心代谢物和核组蛋白乙酰化反应的底物，在代谢-表观遗传轴中扮演着关键角色。最近的证据表明，负责生成乙酰辅酶a的酶可以转移到细胞核，支持亚细胞局部乙酰辅酶a的生产。在这里，我们探讨了乙酰辅酶a代谢对不同亚细胞区室内T细胞功能的影响，并强调了在T细胞驱动的自身免疫性疾病和癌症中干预乙酰辅酶a代谢途径的潜力。

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引用次数: 0

Functional avidity enhancement of a T-cell receptor targeting the KRASG12D cancer neoantigen 靶向KRASG12D肿瘤新抗原的t细胞受体的功能增强

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-06-23 DOI: 10.1016/j.cellimm.2025.104999

Feiyang Luo , Qiwen Yao , Yanan Hao , Meiying Shen , Tong Chen , Ruixin Wu , Tingting Li , Xiaojian Han , Aishun Jin

Engineered T cell receptors (TCRs) targeting neoantigens represent a transformative approach in cancer immunotherapy, yet their clinical potential is limited by low natural TCR avidity and the risk of off-target toxicity from over-engineered TCRs with excessive high-affinity. Here, we developed a TCR engineering platform to enhance the functional avidity of a TCR targeting the KRAS G12D mutation (KRAS^G12D) while avoiding reactivity to the wild-type (WT) peptide. We separately constructed CDR3α- and CDR3β-focused TCR libraries derived from an HLA-A*11:01-restricted KRAS^G12D-specific TCR and screened them using alternating positive and negative selection: KRAS^G12D-pulsed antigen-presenting cells (APCs) drove functional avidity, while KRAS^WT-pulsed APCs eliminated cross-reactive clones. From these libraries, we identified CDR3α variants with modest avidity gains and reduced off-target reactivity, and CDR3β variants with significant avidity enhancement and potent tumor cytotoxicity, albeit with variable cross-reactivity profiles. This strategy enables precision engineering of neoantigen-specific TCRs, balancing therapeutic efficacy and safety for adoptive transfer TCR-T therapy.

靶向新抗原的工程化T细胞受体（TCRs）代表了癌症免疫治疗的一种变革性方法，但其临床潜力受到天然TCR的低亲和力和过高亲和力的过度工程化TCRs脱靶毒性风险的限制。在这里，我们开发了一个TCR工程平台，以增强靶向KRASG12D突变（KRASG12D）的TCR的功能亲和性，同时避免对野生型（WT）肽的反应性。我们从HLA-A*11:01限制性krasg12d特异性TCR中分别构建了CDR3α-和cdr3 β-聚焦的TCR文库，并采用交替阳性和阴性选择对它们进行筛选：krasg12d脉冲抗原呈递细胞（APCs）驱动功能亲和度，而kraswt脉冲APCs消除交叉反应克隆。从这些文库中，我们发现CDR3α变体具有适度的贪婪增益和降低的脱靶反应性，CDR3β变体具有显著的贪婪增强和强大的肿瘤细胞毒性，尽管具有不同的交叉反应性。这种策略使新抗原特异性tcr的精确工程，平衡治疗效果和安全性的过继转移TCR-T治疗。

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引用次数: 0

M6A methyltransferase ZC3H13-mediated downregulation of GPX4 mRNA stability inhibits the progression of kidney renal clear cell carcinoma (KIRC) M6A甲基转移酶zc3h13介导的GPX4 mRNA稳定性下调抑制肾透明细胞癌（KIRC）的进展

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-06-19 DOI: 10.1016/j.cellimm.2025.104998

Dongli Ruan , Rui Huang , Huilong Wang , Kepu Liu , Yi Huang , Zhibin Li

Background

Kidney renal clear cell carcinoma (KIRC) is one of the fatal genitourinary diseases and accounts for most malignant kidney tumors. Previous studies have indicated that RNA modification N6-methyladenosine zinc-finger CCCH-type containing 13 (ZC3H13) plays a vital regulatory role in KIRC. However, the biological role and mechanism of ZC3H13 in KIRC are poorly defined.

Methods

TIMER, ENCORI, and UALCAN databases were used to analyze the expression feature and prognostic significance of ZC3H13. ZC3H13 and Glutathione Peroxidase 4 (GPX4) mRNA level and protein level were determined using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. Cell proliferation and apoptosis were measured using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), and flow cytometry. A xenograft model analyzed the effects of ZC3H13 on tumor growth in vivo. Superoxide dismutase (SOD) activity, Glutathione (GSH) level, and Reactive oxygen species (ROS) were determined using special assay kits. Adenosine triphosphate (ATP) level was detected using kit. Mitochondrial membrane potential changes were analyzed using flow cytometry.

Results

ZC3H13 was decreased, and GPX4 was increased in KIRC tissues and cells. Moreover, overexpressing ZC3H13 hindered KIRC cell proliferation, promoted apoptosis, oxidative stress, and disrupted mitochondrial function in vitro, as well as blocked tumor growth in vivo. At the molecular level, ZC3H13 could decrease the stability and expression of GPX4 mRNA via m6A methylation.

Conclusion

ZC3H13 destabilizes GPX4 mRNA in an m6A-dependent manner, thereby repressing KIRC cell proliferation, expediting apoptosis, oxidative stress, and impairing mitochondrial function, which provided a promising therapeutic target for KIRC.

肾透明细胞癌（KIRC）是致死性泌尿生殖系统疾病之一，是最常见的恶性肾脏肿瘤。已有研究表明，RNA修饰n6 -甲基腺苷锌指型含13 （ZC3H13）在KIRC中起着至关重要的调控作用。然而，ZC3H13在KIRC中的生物学作用和机制尚不明确。方法采用timer、ENCORI、UALCAN数据库分析ZC3H13的表达特征及预后意义。采用实时定量聚合酶链反应（RT-qPCR）和western blot检测ZC3H13和谷胱甘肽过氧化物酶4 (GPX4) mRNA和蛋白表达水平。采用细胞计数试剂盒-8 （CCK-8）、5-乙基-2′-脱氧尿苷（EdU）和流式细胞术检测细胞增殖和凋亡。异种移植瘤模型分析了ZC3H13对肿瘤生长的影响。超氧化物歧化酶（SOD）活性、谷胱甘肽（GSH）水平和活性氧（ROS）采用专用试剂盒检测。采用试剂盒检测三磷酸腺苷（ATP）水平。流式细胞术分析线粒体膜电位变化。结果KIRC组织和细胞中zc3h13表达降低，GPX4表达升高。此外，过表达ZC3H13在体外抑制KIRC细胞增殖、促进细胞凋亡、氧化应激、破坏线粒体功能，在体内阻断肿瘤生长。在分子水平上，ZC3H13可以通过m6A甲基化降低GPX4 mRNA的稳定性和表达。结论zc3h13以m6a依赖的方式破坏GPX4 mRNA的稳定性，从而抑制KIRC细胞增殖、加速细胞凋亡、氧化应激、损害线粒体功能，为KIRC提供了一个有希望的治疗靶点。

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引用次数: 0

Quercetin alleviates diabetic nephropathy by inhibiting M1 macrophage polarization via targeting NLRC5/NLRP3 pathway 槲皮素通过靶向NLRC5/NLRP3通路抑制M1巨噬细胞极化，缓解糖尿病肾病

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-06-17 DOI: 10.1016/j.cellimm.2025.104997

Abudoushalamu Abudoureyimu , Chen Chen , Yan Hu , Dilihumaer Nuermaimaiti , Tao Liu

Background

The activation imbalance of M1/M2 macrophage phenotypes is crucial in diabetic nephropathy (DN). This study aimed to explore the molecular mechanisms underlying quercetin's action against DN.

Methods

In vitro, RAW 264.7 macrophages were incubated with high glucose (HG) with or without quercetin. Overexpression of NLRC5 was investigated to elucidate the mechanism. M1/M2 macrophage differentiation was assessed by flow cytometry using cell surface markers CD86 and CD206. In vivo, a DN mouse model was created using a high-fat diet and streptozotocin (STZ). Quercetin was administered intragastrically to DN mice at 50 mg/kg and 100 mg/kg. After euthanasia, mouse kidneys were analyzed by hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemistry (IHC) staining. ELISA assay and western blot analysis were performed to determine related molecular levels.

Results

In vitro, quercetin significantly reduced HG-induced expressions of CD86, iNOS, NLRC5, NLRP3, and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), while increasing HG-induced CD206, Arg-1, and IL-10 in RAW 264.7 macrophages. However, these effects of quercetin were abolished when NLRC5 was overexpressed. In DN mice, quercetin administration ameliorated renal histopathological injury and fibrosis. Notably, there was a significant reduction in expressions of NLRC5, NLRP3, Col1a1, and α-SMA, along with decreased expressions of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β).

Conclusion

This study showed that quercetin improves DN by inhibiting M1-type macrophages through targeting the NLRC5/NLRP3 pathway.

M1/M2巨噬细胞表型的激活失衡在糖尿病肾病（DN）中至关重要。本研究旨在探讨槲皮素抗DN的分子机制。方法在体外用槲皮素或不加槲皮素培养高糖（HG）巨噬细胞。研究了NLRC5的过表达以阐明其机制。采用细胞表面标志物CD86和CD206，流式细胞术评估M1/M2巨噬细胞分化情况。在体内，采用高脂肪饮食和链脲佐菌素（STZ）建立DN小鼠模型。槲皮素分别以50 mg/kg和100 mg/kg剂量灌胃DN小鼠。安乐死后，用苏木精和伊红（H&；E）、马松三色和免疫组织化学（IHC）染色对小鼠肾脏进行分析。ELISA法和western blot法检测相关分子水平。结果槲皮素在体外显著降低hg诱导的巨噬细胞CD86、iNOS、NLRC5、NLRP3和促炎细胞因子（TNF-α、IL-6、IL-1β）的表达，升高hg诱导的RAW 264.7巨噬细胞CD206、Arg-1和IL-10的表达。然而，当NLRC5过表达时，槲皮素的这些作用被消除。在DN小鼠中，槲皮素可改善肾组织病理学损伤和纤维化。值得注意的是，NLRC5、NLRP3、Col1a1和α-SMA的表达显著降低，同时促炎细胞因子（TNF-α、IL-6和IL-1β）的表达降低。结论槲皮素通过靶向NLRC5/NLRP3通路抑制m1型巨噬细胞改善DN。

{"title":"Quercetin alleviates diabetic nephropathy by inhibiting M1 macrophage polarization via targeting NLRC5/NLRP3 pathway","authors":"Abudoushalamu Abudoureyimu , Chen Chen , Yan Hu , Dilihumaer Nuermaimaiti , Tao Liu","doi":"10.1016/j.cellimm.2025.104997","DOIUrl":"10.1016/j.cellimm.2025.104997","url":null,"abstract":"<div><h3>Background</h3><div>The activation imbalance of M1/M2 macrophage phenotypes is crucial in diabetic nephropathy (DN). This study aimed to explore the molecular mechanisms underlying quercetin's action against DN.</div></div><div><h3>Methods</h3><div><em>In vitro</em>, RAW 264.7 macrophages were incubated with high glucose (HG) with or without quercetin. Overexpression of NLRC5 was investigated to elucidate the mechanism. M1/M2 macrophage differentiation was assessed by flow cytometry using cell surface markers CD86 and CD206. <em>In vivo</em>, a DN mouse model was created using a high-fat diet and streptozotocin (STZ). Quercetin was administered intragastrically to DN mice at 50 mg/kg and 100 mg/kg. After euthanasia, mouse kidneys were analyzed by hematoxylin and eosin (H&E), Masson's trichrome, and immunohistochemistry (IHC) staining. ELISA assay and western blot analysis were performed to determine related molecular levels.</div></div><div><h3>Results</h3><div><em>In vitro</em>, quercetin significantly reduced HG-induced expressions of CD86, iNOS, NLRC5, NLRP3, and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), while increasing HG-induced CD206, Arg-1, and IL-10 in RAW 264.7 macrophages. However, these effects of quercetin were abolished when NLRC5 was overexpressed. In DN mice, quercetin administration ameliorated renal histopathological injury and fibrosis. Notably, there was a significant reduction in expressions of NLRC5, NLRP3, Col1a1, and α-SMA, along with decreased expressions of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β).</div></div><div><h3>Conclusion</h3><div>This study showed that quercetin improves DN by inhibiting M1-type macrophages through targeting the NLRC5/NLRP3 pathway.</div></div>","PeriodicalId":9795,"journal":{"name":"Cellular immunology","volume":"414 ","pages":"Article 104997"},"PeriodicalIF":3.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Curcumin mitigates systemic lupus erythematosus by suppressing double-negative T cells through cell apoptosis 姜黄素通过细胞凋亡抑制双阴性T细胞减轻系统性红斑狼疮

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-06-16 DOI: 10.1016/j.cellimm.2025.104996

Min Xu , Xiaoliu Li , Cheng Bao , Yue Zhang , Jinghan Yang , Yang Hang , Lingyun Sun , Hongwei Chen

Objective

Curcumin extracted from the rhizome of Curcuma longa has anti-inflammatory, antioxidant and antitumour properties. In previous studies, curcumin has been reported to have therapeutic effects on systemic lupus erythematosus (SLE), in which the upregulation of double-negative T (DNT) cells was detected. Therefore, the purpose of this study is to explore the role of curcumin in the remission of SLE by regulating DNT cell homeostasis.

Methods

Two established murine models of lupus, MRL/lpr mice and R848-induced mice, were administered with 50 mg/kg curcumin to evaluate its therapeutic effects. Flow cytometry was used to detect the proportions of DNT cells, Treg cells and Th cells in mouse tissues. H&E staining and immunofluorescence were used to assess inflammatory cell infiltration and immune complex deposition in the kidney. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative PCR (RT-qPCR) were used to detect the expression of inflammatory factors. RNA sequencing was used to identify differentially expressed genes and explore regulatory mechanisms, and western blot was used to detect protein expression.

Results

Our results suggest that the accumulation of DNT cells is closely associated with lupus pathogenesis and development in both mouse models, whereas curcumin treatment can improve lupus serological and immunological profiles, and regulate T-cell homeostasis, especially DNT cells. Further studies demonstrated that curcumin promoted DNT cell apoptosis to eventually decrease the accumulation of DNT cells.

Conclusion

Curcumin can improve lupus serological and immunological profiles as well as renal pathology by suppressing DNT cells, and may be a potential candidate for the treatment of SLE.

目的从姜黄根茎中提取姜黄素具有抗炎、抗氧化和抗肿瘤的作用。在以往的研究中，姜黄素被报道对系统性红斑狼疮（SLE）有治疗作用，其中检测到双阴性T （DNT）细胞的上调。因此，本研究的目的是探讨姜黄素通过调节DNT细胞稳态在SLE缓解中的作用。方法建立狼疮模型，MRL/lpr小鼠和r848诱导小鼠分别给予50 mg/kg姜黄素，观察其治疗狼疮的效果。采用流式细胞术检测小鼠组织中DNT细胞、Treg细胞和Th细胞的比例。采用H&；E染色和免疫荧光法评估肾脏炎症细胞浸润和免疫复合物沉积。采用酶联免疫吸附试验（ELISA）和实时定量PCR （RT-qPCR）检测炎症因子的表达。采用RNA测序技术鉴定差异表达基因并探索调控机制，采用western blot技术检测蛋白表达。结果在两种小鼠模型中，DNT细胞的积累与狼疮的发病和发展密切相关，而姜黄素治疗可以改善狼疮的血清学和免疫学特征，调节t细胞稳态，尤其是DNT细胞。进一步研究表明，姜黄素促进DNT细胞凋亡，最终减少DNT细胞的积累。结论姜黄素可通过抑制DNT细胞改善狼疮血清学、免疫学及肾脏病理，可能是治疗狼疮的潜在候选药物。

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引用次数: 0