Cellular immunology最新文献_第2页

Actin cytoskeleton stabilization inhibits NLRP3 inflammasome activation and mitigates renal inflammation and fibrosis in obstructive nephropathy 肌动蛋白细胞骨架稳定抑制NLRP3炎性体激活并减轻阻塞性肾病的肾脏炎症和纤维化。

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-11-21 DOI: 10.1016/j.cellimm.2025.105053

Qiaoli Xu , Jinxin Li , Xing Wan , Gaoling Wang , Jiawei Wu , Xinrui Chang , Fang Yan , Li Li , Baosheng Han

Obstructive nephropathy is characterized by progressive renal inflammation and tubular injury, in which the NLRP3 inflammasome plays a pivotal role. However, the contribution of cytoskeletal dynamics to inflammasome activation remains poorly understood. In this study, we investigated whether stabilizing the actin cytoskeleton using Bis-T-23, a filamentous actin (F-actin) stabilizer, could alleviate renal injury by suppressing NLRP3 signaling. In a unilateral ureteral obstruction (UUO) mouse model, Bis-T-23 treatment significantly reduced tubular dilation, interstitial fibrosis, and immune cell infiltration. Transcriptomic profiling revealed marked downregulation of inflammation-related pathways, including TNF, IL-17, and NOD-like receptor signaling. At the molecular level, Bis-T-23 inhibited NLRP3 inflammasome activation, as evidenced by decreased levels of NLRP3, cleaved caspase-1, IL-1β, and IL-18 in both renal tissue and tubular epithelial cells. In vitro, TNFα/TGFβ1 co-stimulation induced a pro-fibrotic and pro-inflammatory phenotype in tubular cells, characterized by ZO-1 disruption, α-SMA upregulation, and enhanced NLRP3 expression, all of which were reversed by Bis-T-23. Furthermore, Bis-T-23 impaired ASC speck formation and disrupted NLRP3–ASC interactions, suggesting a direct blockade of inflammasome assembly. These findings identify cytoskeletal stabilization as a novel upstream mechanism for NLRP3 regulation and highlight Bis-T-23 as a potential therapeutic candidate for mitigating tubular inflammation in obstructive kidney disease.

梗阻性肾病以进行性肾炎症和肾小管损伤为特征，其中NLRP3炎症小体起关键作用。然而，细胞骨架动力学对炎性小体活化的贡献仍然知之甚少。在这项研究中，我们研究了使用Bis-T-23（一种丝状肌动蛋白（f -肌动蛋白）稳定剂）稳定肌动蛋白细胞骨架是否可以通过抑制NLRP3信号来减轻肾损伤。在单侧输尿管梗阻（UUO）小鼠模型中，Bis-T-23治疗可显著减少小管扩张、间质纤维化和免疫细胞浸润。转录组学分析显示炎症相关通路显著下调，包括TNF、IL-17和nod样受体信号。在分子水平上，Bis-T-23抑制NLRP3炎性体的激活，这可以通过降低肾组织和小管上皮细胞中NLRP3、cleaved caspase-1、IL-1β和IL-18的水平来证明。在体外，tnf - α/ tgf - β1共刺激诱导小管细胞的促纤维化和促炎表型，其特征是ZO-1破坏，α-SMA上调，NLRP3表达增强，所有这些都被Bis-T-23逆转。此外，Bis-T-23损伤了ASC斑点的形成，破坏了NLRP3-ASC的相互作用，这表明它直接阻断了炎症小体的组装。这些发现确定细胞骨架稳定是NLRP3调控的一个新的上游机制，并强调Bis-T-23是缓解梗阻性肾病小管炎症的潜在治疗候选药物。

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引用次数: 0

Peiminine modulates T cell-associated gene expression and inflammatory activity in experimental autoimmune hepatitis 实验性自身免疫性肝炎中贝胺碱调节T细胞相关基因表达和炎症活性。

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-11-20 DOI: 10.1016/j.cellimm.2025.105055

Amin Azizan , Mohammad Ali Abyazi , Seyed Kiarash Aghayan , Majid Mirzaei Nodooshan , Akbar Ghorbani Alvanegh , Hadi Esmaeili Gouvarchin Ghaleh

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by immune-mediated hepatocellular injury and insufficient regulatory T cell (Treg) control. Despite the efficacy of corticosteroids and azathioprine, incomplete response, side effects, and relapse often limit treatment, underscoring the need for novel therapeutic strategies. To date, little is known about the potential of natural compounds in modulating T cell–related pathways in AIH.

This study aimed to evaluate the therapeutic effects of peiminine, an alkaloid with reported anti-inflammatory and immunomodulatory properties, in an experimental model of AIH. We investigated its impact on liver histopathology, inflammatory markers, and expression of T cell–associated genes (FOXP3, Tbx21, and RORc), comparing its efficacy with prednisolone.

Our results demonstrated that peiminine treatment significantly alleviated interface hepatitis, reduced inflammatory cell infiltration, and improved lobular architecture. Quantitative histological scoring confirmed that peiminine, particularly at higher doses, exerted protective effects comparable to prednisolone. At the molecular level, peiminine increased FOXP3 expression while suppressing Tbx21 and RORc, suggesting restoration of Treg/Th1/Th17 balance. These findings were consistent with reductions in pro-inflammatory cytokine expression and improved liver function indices.

Collectively, our findings provide promising preclinical evidence that peiminine can attenuate autoimmune-mediated liver injury by modulating T cell–associated immune pathways. While further validation in human studies is necessary, these results identify peiminine as a potential adjunct or alternative therapeutic candidate for AIH, with implications for broader autoimmune disease management.

自身免疫性肝炎（AIH）是一种以免疫介导的肝细胞损伤和调节性T细胞（Treg）控制不足为特征的慢性炎症性肝病。尽管皮质类固醇和硫唑嘌呤有效，但不完全缓解、副作用和复发往往限制了治疗，强调需要新的治疗策略。迄今为止，关于天然化合物在AIH中调节T细胞相关通路的潜力知之甚少。本研究旨在评价贝亚胺（一种具有抗炎和免疫调节特性的生物碱）在AIH实验模型中的治疗效果。我们研究了其对肝脏组织病理学、炎症标志物和T细胞相关基因（FOXP3、Tbx21和RORc）表达的影响，并将其与强的松龙的疗效进行了比较。我们的研究结果表明，培咪明治疗可显著缓解界面肝炎，减少炎症细胞浸润，改善小叶结构。定量组织学评分证实，贝亚明，特别是在高剂量时，具有与强的松龙相当的保护作用。在分子水平上，贝亚胺增加FOXP3的表达，同时抑制Tbx21和RORc，提示Treg/Th1/Th17平衡的恢复。这些发现与促炎细胞因子表达减少和肝功能指数改善一致。总的来说，我们的研究结果提供了有希望的临床前证据，表明贝胺明可以通过调节T细胞相关的免疫途径来减轻自身免疫介导的肝损伤。虽然需要在人体研究中进一步验证，但这些结果确定了贝亚明作为AIH的潜在辅助或替代治疗候选药物，具有更广泛的自身免疫性疾病管理意义。

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引用次数: 0

Exosomes derived from ovarian cancer promote the progression of ovarian cancer through macrophage M2 polarization mediated by the THBS1/TGFBI signaling axis 来自卵巢癌的外泌体通过THBS1/TGFBI信号轴介导的巨噬细胞M2极化促进卵巢癌的进展

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-11-19 DOI: 10.1016/j.cellimm.2025.105054

Linlin Yang, Yue Jia, Ying Liu, Shaojia Wang, Shufen Tan, Youqin Ruan, Lingfeng Zhao, He Zhao, Ruolan Xu, Chunyan Ding, Hui Liu, Yan Qin, Haijuan Zhao, Xinyue Feng, Changyi Zeng, Yuye Li, Xiang Meng, Hongying Yang

Background

Tumor-derived exosomes play a critical role in facilitating intercellular communication between cancer cells and tumor-associated macrophages (TAMs). Nevertheless, the precise molecular mechanisms underlying exosome-mediated interactions specifically in ovarian cancer remain incompletely elucidated.

Methods

TAMs were treated with exosomes isolated from clinical ovarian cancer specimens. Macrophage polarization was assessed using qRT-PCR, and western blot analysis. RNA sequencing was employed to identify key genes within the exosomes. The malignant phenotype of ovarian cancer cells was evaluated through cell counting kit-8 (CCK-8), Transwell assay, and wound-healing assays.

Results

Our findings showed that exosomes derived from both early and late-stage malignant ovarian cancer tissues induced the upregulation of all M2 macrophage markers and the downregulation of M1 markers. RNA sequencing analysis identified thrombospondin-1 (THBS1) as a potential pivotal gene influencing exosome-regulated TAM polarization. THBS1 knockdown within exosomes inhibited the polarization of TAMs toward the M2 phenotype and concurrently decreased transforming growth factor beta induced (TGFBI) expression in macrophages. Notably, TGFBI knockdown in TAM reversed the M2 polarization induced by ovarian cancer cells-derived exosomes. In vivo, ovarian cancer cell-derived exosomes facilitate cancer progression, concomitantly increasing the polarization of M2 macrophages and upregulating THBS1 and TGFBI expression within tumor tissues.

Conclusion

THBS1, carried by ovarian cancer-derived exosomes, promotes M2 polarization of TAMs by modulating TGFBI expression. The subsequent M2 polarization of TAMs contributes to the establishment of an immunosuppressive tumor microenvironment, thereby facilitating disease progression. Consequently, targeting the exosome-mediated signaling axis between cancer cells and macrophages represents a promising avenue for developing novel therapeutic interventions.

肿瘤来源的外泌体在促进癌细胞和肿瘤相关巨噬细胞（tam）之间的细胞间通讯中起着关键作用。然而，外泌体介导的相互作用在卵巢癌中的确切分子机制仍未完全阐明。方法用临床卵巢癌标本分离的外泌体处理stams。采用qRT-PCR和western blot分析巨噬细胞极化。RNA测序用于鉴定外泌体中的关键基因。通过细胞计数试剂盒-8 （CCK-8）、Transwell实验和伤口愈合实验评估卵巢癌细胞的恶性表型。结果发现，来自早期和晚期恶性卵巢癌组织的外泌体诱导所有M2巨噬细胞标志物上调，M1标志物下调。RNA测序分析发现血栓反应蛋白-1 （THBS1）是影响外泌体调节的TAM极化的潜在关键基因。外泌体内THBS1的敲低抑制了tam向M2表型的极化，同时降低了巨噬细胞中转化生长因子β诱导（TGFBI）的表达。值得注意的是，TAM中TGFBI的敲低逆转了卵巢癌细胞源性外泌体诱导的M2极化。在体内，卵巢癌细胞源性外泌体促进癌症进展，同时增加M2巨噬细胞的极化，上调肿瘤组织中THBS1和TGFBI的表达。结论卵巢癌源性外泌体携带thbs1通过调节TGFBI的表达促进TAMs的M2极化。随后tam的M2极化有助于建立免疫抑制的肿瘤微环境，从而促进疾病进展。因此，靶向癌细胞和巨噬细胞之间的外泌体介导的信号轴代表了开发新的治疗干预措施的有希望的途径。

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引用次数: 0

The discovery of regulatory T cells: a paradigm shift in immunology. 调节性T细胞的发现：免疫学的范式转变。

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-11-10 DOI: 10.1016/j.cellimm.2025.105049

Simon Fillatreau, Yi Hao

The immune system is conventionally viewed as an army of fighters present naturally in an inactive state, ready to react to microbial invasion. Activation follows the detection of microbial molecules either by innate receptors, which are broadly expressed across cell types, or by antigen-specific receptors - the T cell receptor (TCR) and B cell receptor (BCR) - exclusively found on T and B lymphocytes, respectively. Previously to the discovery of regulatory T cells (Tregs), the induction of immune responses was thought to be controlled exclusively by the provision of activation signals coming from "outside" of the immune system. The discovery of regulatory T cells (Tregs) revealed a radically different mode of immune control. It emphasized immune activation as the default phenomenon at steady state, underlining suppression as essential to maintain immune homeostasis. Under this new view, the induction of immune response can proceed without external signal, upon the removal of key immune breaks internal to the immune system and embodied by Tregs. It fundamentally transformed our understanding of immune regulation and opened new therapeutic avenues for diseases ranging from autoimmunity to cancer. The immense impact of this work was rewarded this year by the attribution of the Nobel prize of Physiology and Medicine to Prof. Shimon Sakaguchi, Prof. Mary E. Brunkow, and Prof. Fred Ramsdell. In this article, we outline the scientific context of these discoveries in the 1990s, and discuss their impact for our understanding of the immune system and the development of novel therapies.

免疫系统通常被视为一群处于不活跃状态的战士，随时准备对微生物的入侵做出反应。微生物分子的激活可以通过先天受体（广泛表达于各种细胞类型）或抗原特异性受体（T细胞受体（TCR）和B细胞受体（BCR））进行检测，这两种受体分别只存在于T淋巴细胞和B淋巴细胞上。在发现调节性T细胞（Tregs）之前，免疫反应的诱导被认为完全由提供来自免疫系统“外部”的激活信号来控制。调节性T细胞（Tregs）的发现揭示了一种完全不同的免疫控制模式。它强调免疫激活是稳定状态下的默认现象，强调抑制是维持免疫稳态的必要条件。在这种新的观点下，免疫反应的诱导可以在没有外部信号的情况下进行，只要清除免疫系统内部的关键免疫断裂，并以Tregs为代表。它从根本上改变了我们对免疫调节的理解，并为从自身免疫到癌症等疾病开辟了新的治疗途径。这项工作的巨大影响今年被授予诺贝尔生理学和医学奖给Shimon Sakaguchi教授，Mary E. Brunkow教授和Fred Ramsdell教授。在本文中，我们概述了20世纪90年代这些发现的科学背景，并讨论了它们对我们对免疫系统的理解和新疗法发展的影响。

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引用次数: 0

Evaluating the impact of using bone marrow-derived macrophages to turn early tumor sites into hot early tumor sites 评估骨髓源性巨噬细胞将早期肿瘤部位转化为热早期肿瘤部位的影响。

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-11-08 DOI: 10.1016/j.cellimm.2025.105050

Joshua Finn, Emily Kessler, Melissa Lass, Ernesto Oviedo-Bermudez, Robert A. Kurt

The impact of transforming an early tumor site into a hot early tumor site was evaluated using bone marrow-derived macrophages (BMDM) activated with IFN-γ and sCD40L in combination with Toll-like receptor (TLR) agonists (lipopolysaccharide (LPS), flagellin or R848). Not surprisingly, analysis of the activated BMDM revealed characteristics often ascribed to anti-tumor (M1) macrophages with production of nitrite and IL-12, as well as expression of Il-1b, Il-6, Tnf-a, Il-18, Ccl5, Cxcl9, Cxcl10, and Cxcl11. All treatments also led to a significant increase in MHC Class II or CD80 expression, but only BMDM activated with IFN-γ and LPS showed a significant increase in both MHC Class II and CD80 expression. Delivering these BMDM to early tumor sites slowed progression of three murine mammary carcinoma models (EMT6, 168, 4 T1). Depletion studies revealed that the anti-tumor activity was dependent upon CD8⁺ T cells and NK cells suggesting that expression of Ccl5, Cxcl9, Cxcl10, and/or Cxcl11 may be important for the in vivo function of the BMDM. Additionally, inhibiting G protein coupled receptor (GPCR) signaling in the BMDM ablated the anti-tumor activity suggesting that the anti-tumor activity may be dependent on the migratory ability of the BMDM. Collectively, these data show that creating hot early tumor sites by delivering anti-tumor BMDM can impact tumor growth by eliciting CD8⁺ T cells and NK cells, and that BMDM anti-tumor activity depends on GPCR-mediated signaling.

利用IFN-γ和sCD40L联合toll样受体（TLR）激动剂（脂多糖（LPS）、鞭毛蛋白或R848）激活的骨髓源性巨噬细胞（BMDM），评估将早期肿瘤部位转化为热早期肿瘤部位的影响。毫不奇怪，对活化BMDM的分析揭示了抗肿瘤（M1）巨噬细胞产生亚硝酸盐和IL-12以及表达Il-1b、Il-6、Tnf-a、Il-18、Ccl5、Cxcl9、Cxcl10和Cxcl11的特征。所有处理也导致MHC II类或CD80表达显著增加，但只有IFN-γ和LPS激活的BMDM显示MHC II类和CD80表达显著增加。将这些BMDM输送到早期肿瘤部位可以减缓三种小鼠乳腺癌模型的进展（EMT6, 168, 4 T1）。耗尽研究显示，抗肿瘤活性依赖于CD8+ T细胞和NK细胞，这表明Ccl5、Cxcl9、Cxcl10和/或Cxcl11的表达可能对BMDM的体内功能很重要。此外，抑制BMDM中的G蛋白偶联受体（GPCR）信号通路会降低其抗肿瘤活性，提示其抗肿瘤活性可能依赖于BMDM的迁移能力。综上所述，这些数据表明，通过传递抗肿瘤BMDM创建热早期肿瘤位点可以通过诱导CD8+ T细胞和NK细胞影响肿瘤生长，并且BMDM抗肿瘤活性依赖于gpcr介导的信号传导。

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引用次数: 0

The inflammatory effects of a repeated exposure of human macrophages to PM2.5 from house dust-SRM 2585 are partially reversible and disrupt the LPS/CD14 signaling pathways 人类巨噬细胞反复暴露于室内灰尘PM2.5 （srm 2585）的炎症效应是部分可逆的，并破坏LPS/CD14信号通路

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-11-07 DOI: 10.1016/j.cellimm.2025.105048

Lelong Marie , Morin Laura , Pottier Ivannah , Andre Véronique , Lecureur Valérie

Objectives

To evaluate whether repeated exposures to house dust PM_2.5, used at nontoxic concentrations, activate human macrophages after one- and seven-days post-treatment, and whether such PM_2.5 exposure may alter their response to LPS.

Methods

Human monocyte-derived macrophages (MDMs) were repeatedly (4 consecutive days) exposed to 1 and 10 μg/cm² house dust PM_2.5 fraction of SRM 2585®. MDM phenotype and functions were evaluated by flow cytometry and ELISA one- and seven-days after the last PM_2.5 exposure with or without LPS priming during the last 24 h of exposure.

Results

PM_2.5 used at non cytotoxic concentrations induced a pro-inflammatory phenotype characterized by an increased expression of M1 macrophagic markers (CD40, CD80, CD86) and pro-inflammatory cytokines (IL-6, IL-8, TNFα) and a decreased expression of M2 macrophagic markers (CD163, CD204) and of the anti-inflammatory cytokine IL-10, however depending of post-exposure time and the concentration. PM_2.5-induced polarization profile of MDM was reversible when they were exposed to 1 μg/cm² but not to 10 μg/cm². PM_2.5-primed MDMs and then exposed to LPS showed a pro-inflammatory phenotype characterized by altered secretion of IL-8 and IL-10, a decreased expression of CD14, scavenger receptors (SR)-A1 and interferon responsive genes (CXCL9/10, ISG15) and a decrease of endocytosis and phagocytosis of bacteria.

Conclusions

Repeated exposures, even to low concentration of house dust PM_2.5, primed MDMs to a pro-inflammatory phenotype that is only partly reversible seven days post-exposure. The altered response of PM_2.5-pre-exposed MDMs to LPS might be due to, at least in part, impaired endocytosis crucial for the TLR4/CD14 pathway.

目的评估反复暴露于无毒浓度的室内粉尘PM2.5是否会在处理后1天和7天后激活人类巨噬细胞，以及这种PM2.5暴露是否会改变它们对LPS的反应。方法将人单核细胞源性巨噬细胞（MDMs）连续4天反复暴露于1和10 μg/cm2的SRM 2585®室内粉尘PM2.5组分。结果非细胞毒性浓度的spm2.5可诱导促炎表型，其特征是M1巨噬细胞标志物（CD40、CD80、CD86）和促炎细胞因子（IL-6、IL-8、TNFα）的表达增加，M2巨噬细胞标志物(CD163、CD204)和抗炎细胞因子IL-10，但取决于暴露后的时间和浓度。当pm2.5浓度为1 μg/cm2时，MDM的极化曲线是可逆的，而当pm2.5浓度为10 μg/cm2时则不可逆。pm2.5引发的MDMs暴露于LPS后表现出促炎表型，其特征是IL-8和IL-10的分泌改变，CD14、清零受体(SR)-A1和干扰素应答基因（CXCL9/10、ISG15）的表达降低，细菌的内吞和吞噬减少。反复暴露，即使是低浓度的室内粉尘PM2.5，也会使MDMs产生促炎表型，而这种表型在暴露7天后只能部分逆转。pm2.5预先暴露的MDMs对LPS的反应改变可能是由于TLR4/CD14途径至关重要的内吞作用受损，至少部分原因是。

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引用次数: 0

Immunomodulatory effects of mesenchymal stromal cell secretome accelerate repair in a sickle cell disease wound model 间充质基质细胞分泌组的免疫调节作用加速镰状细胞病伤口模型的修复

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-11-04 DOI: 10.1016/j.cellimm.2025.105047

Brysa M. Silveira , Tiago O. Ribeiro , Songeli M. Freire , Beatriz Costa , Vitor Valério Maffili , Marilda Souza Gonçalves , Mari Sogayar , Roberto José Meyer Nascimento , Vitor Fortuna

Chronic leg ulcers (CLUs) are a debilitating complication of sickle cell disease (SCD), driven by persistent inflammation, immune dysregulation, and vascular dysfunction. Current therapies fail to correct the hostile immune microenvironment that impairs repair. Here, we investigated the therapeutic potential of the adipose-derived mesenchymal stromal cell (ASC) secretome as a cell-free immunomodulatory approach in a preclinical SCD wound model. Full-thickness excisional wounds were induced in Townes HbSS mice and treated topically with ASC secretome or vehicle control. Treatment accelerated wound closure, enhanced re-epithelialization, and reduced inflammatory infiltrates. Histology revealed advanced collagen deposition and matrix organization, while immunofluorescence demonstrated increased CD31, α-SMA, and SM22 expression, indicating neovascularization and perivascular maturation. Gene expression profiling showed early upregulation of IL-10, TGF-β, and ARG1 and later downregulation of TNF, IL-1β, and NOS2, reflecting a shift toward a reparative immune milieu. Increased F4/80⁺ macrophages together with elevated CD31⁺ vascular markers were consistent with immune–vascular interactions. Collectively, these findings demonstrate that ASC secretome restores immune balance, supports vascular integrity, and promotes tissue regeneration in SCD-associated chronic wounds. This study provides preclinical evidence for ASC secretome as a promising, scalable, and cell-free immunomodulatory therapy for refractory chronic wounds.

慢性腿部溃疡（CLUs）是镰状细胞病（SCD）的一种衰弱性并发症，由持续炎症、免疫失调和血管功能障碍驱动。目前的治疗方法无法纠正损害修复的敌对免疫微环境。在这里，我们研究了脂肪来源的间充质基质细胞（ASC）分泌组作为无细胞免疫调节方法在临床前SCD伤口模型中的治疗潜力。在Townes HbSS小鼠中诱导全层切除伤口，并用ASC分泌组或对照物局部治疗。治疗加速伤口愈合，增强再上皮化，减少炎症浸润。组织学显示胶原沉积和基质组织进展，免疫荧光显示CD31、α-SMA和SM22表达增加，表明新生血管和血管周围成熟。基因表达谱显示早期IL-10、TGF-β和ARG1上调，随后TNF、IL-1β和NOS2下调，反映了向修复性免疫环境的转变。F4/80+巨噬细胞的增加和CD31+血管标志物的升高与免疫-血管相互作用一致。总的来说，这些发现表明ASC分泌组在scd相关的慢性伤口中恢复免疫平衡，支持血管完整性，促进组织再生。本研究为ASC分泌组作为一种有前景的、可扩展的、无细胞的免疫调节疗法治疗难治性慢性伤口提供了临床前证据。

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引用次数: 0

Mesenchymal stromal cells relieved systemic lupus erythematosus via CCL2 dependent macrophage polarization 间充质间质细胞通过CCL2依赖性巨噬细胞极化缓解系统性红斑狼疮。

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-10-30 DOI: 10.1016/j.cellimm.2025.105046

Xin Wen , Genhong Yao , Yujie Zhou , Shanshan Liu , Lingyun Sun

Systemic lupus erythematosus (SLE) was an autoimmune disease leading to high morbidity and mortality without effective and low-side effect conventional drugs. Our previous clinical studies demonstrated umbilical cord derived mesenchymal stromal cells (MSCs) were a safe and effective treatment, but its therapeutic mechanism is still unclear. In this study, we first observed clinical used MSCs exhibited higher CCL2 expression than primary and aged MSCs, and abnormal bone marrow derived MSC (BM-MSC) from SLE patients performed decreased CCL2 expression compared to healthy control. Then, we constructed CCL2-deficient MSCs, and found the immunosuppressive activity of CCL2-deficient MSCs was impaired in the peripheral blood mononuclear cell (PBMC) inhibitory assay in vitro. CCL2-deficient MSCs also failed to relieve SLE in MRL/lpr and pristine-induced mice. To further explore the role of CCL2 in MSC therapy, we performed transcriptomic profiling of CCL2-deficient MSCs and MSCs, and identified the differential expressed genes were related to chemotaxis, including monocyte chemotaxis. Subsequently, we found that MSCs restored the imbalance in M1/M2 macrophage polarization via CCL2 in vitro. These findings provided valuable insight for investigating the therapeutic mechanism of MSC on SLE.

系统性红斑狼疮（SLE）是一种自身免疫性疾病，发病率高、死亡率高，常规药物疗效低、副作用小。我们之前的临床研究表明，脐带间充质间质细胞（MSCs）是一种安全有效的治疗方法，但其治疗机制尚不清楚。在这项研究中，我们首次观察到临床使用的MSCs比原代和衰老的MSCs具有更高的CCL2表达，而来自SLE患者的异常骨髓来源的MSC （BM-MSC）与健康对照相比，CCL2表达降低。然后构建ccl2缺陷MSCs，在体外外周血单核细胞（PBMC）抑制实验中发现ccl2缺陷MSCs的免疫抑制活性受损。缺乏ccl2的MSCs也未能缓解MRL/lpr和原始诱导小鼠的SLE。为了进一步探索CCL2在MSC治疗中的作用，我们对缺乏CCL2的MSCs和MSCs进行了转录组学分析，并确定了与趋化性相关的差异表达基因，包括单核细胞趋化性。随后，我们发现MSCs在体外通过CCL2修复了巨噬细胞M1/M2极化失衡。这些发现为研究MSC对SLE的治疗机制提供了有价值的见解。

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引用次数: 0

Differential heterologous immunological effects induced by ChAdOx1-S and BNT162b2 COVID-19 vaccines ChAdOx1-S和BNT162b2疫苗诱导的异源免疫效应

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-10-27 DOI: 10.1016/j.cellimm.2025.105038

Elisabeth A. Dulfer , Büsra Geckin , Martijn Zoodsma , Leonie S. Helder , Wenchao Li , Reinout van Crevel , Josephine S. van der Maat , Yang Li , Jorge Domínguez-Andrés , Mihai G. Netea

Background

The mRNA- and adenovirus-based COVID-19 vaccines may induce different heterologous effects on non-COVID morbidity. We aimed to investigate immunological mechanisms that may account for these differences.

Methods

We selected a subgroup of individuals from the TACTIC trial who had completed their COVID-19 vaccination scheme before the introduction of a BNT162b2 booster vaccine. Transcriptional activity, distribution of cell types and cytokine secretion were compared between those who were originally vaccinated with the adenovirus vaccine ChAdOx1-S, and those who had received the mRNA vaccine BNT162b2. Additionally, we investigated how these differences evolved after administration of a BNT162b2 booster vaccine.

Results

24 individuals were included in this study, with 15 volunteers (62.5%) having originally received an mRNA vaccine and 9 (37.5%) an adenovirus vector vaccine. We found that 84 gene sets were differentially expressed in PBMCs from the two vaccine groups following ex-vivo secondary stimulation. Although cell populations did not significantly differ, pro-inflammatory cytokine responses to most stimuli were consistently higher in the adenovirus group compared to the mRNA group. These differences decreased after an mRNA booster vaccine.

Discussion

Our study findings provide additional support to the hypothesis that mRNA- and adenovirus-based vaccines differ in their broad immunological effects. Specifically, our observation that adenovirus-based vaccination tends to result in higher pro-inflammatory cytokine responses might help explain the difference in the heterologous effects of the two types of vaccines. Knowledge about NSEs is increasingly important for making public health and policy decisions, particularly for vulnerable populations.

背景：基于mRNA和腺病毒的COVID-19疫苗可能对非COVID-19发病率产生不同的异源效应。我们的目的是研究可能解释这些差异的免疫学机制。方法：我们从战术试验中选择了一组在引入BNT162b2加强疫苗之前完成COVID-19疫苗接种计划的个体。比较了最初接种腺病毒疫苗ChAdOx1-S和mRNA疫苗BNT162b2的转录活性、细胞类型分布和细胞因子分泌情况。此外，我们研究了在接种BNT162b2加强疫苗后这些差异是如何演变的。结果：本研究纳入了24人，其中15名志愿者（62.5%）最初接种了mRNA疫苗，9名志愿者（37.5%）接种了腺病毒载体疫苗。我们发现，在离体二次刺激后，来自两个疫苗组的pbmc中有84组基因组存在差异表达。虽然细胞群没有显著差异，但与mRNA组相比，腺病毒组对大多数刺激的促炎细胞因子反应始终较高。这些差异在mRNA增强疫苗后减少。讨论：我们的研究结果为基于mRNA的疫苗和基于腺病毒的疫苗在其广泛的免疫效果上不同的假设提供了额外的支持。具体来说，我们观察到基于腺病毒的疫苗接种倾向于导致更高的促炎细胞因子反应，这可能有助于解释两种类型疫苗的异源效应差异。对于公共卫生和政策决策的制定，特别是对弱势群体而言，关于国家社会安全措施的知识越来越重要。

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引用次数: 0

Macrophages: Traffic centers in the tumor immune microenvironment 巨噬细胞：肿瘤免疫微环境的交通中心

IF 2.9 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2025-10-09 DOI: 10.1016/j.cellimm.2025.105037

Fan Zou, Yishan Zhang, Mingdong Wang, Yongjun Quan, Hao Ping

The tumor microenvironment (TME) has emerged as a prominent focus of cancer research in recent years, with various drugs in this field, including programmed cell death receptor 1 (PD-1) antibodies and cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies, now included in first-line therapeutic guidelines for cancer. Although macrophages are not as effective as T-lymphocytes in directly killing tumors, they serve as critical mediators in the TME due to their indirect roles in promoting blood vessel formation, facilitating antigen presentation and influencing tumor cell metabolism to affect their infiltration. Macrophages are governed by complex regulatory networks, both independently and as a part of the TME. Extensive research has led to the development of a comprehensive and detailed understanding of these networks and the molecular mechanisms driving macrophage activity. The interactions between macrophages and the TME significantly impact tumor initiation and progression, making macrophages a promising target for cancer therapy. In this review, we discuss recent findings on the factors underlying macrophage polarization in the TME, the critical role of macrophages within the TME, key transcriptional regulators of macrophages, and emerging strategies for targeting macrophages in cancer therapy.

肿瘤微环境（tumor microenvironment， TME）近年来已成为癌症研究的一个突出焦点，包括程序性细胞死亡受体1 （programmed cell death receptor 1, PD-1）抗体和细胞毒性T淋巴细胞抗原4 （cytotoxic T lymphocyte antigen 4, CTLA-4）抗体在内的多种药物现已被纳入癌症一线治疗指南。虽然巨噬细胞在直接杀伤肿瘤方面不如t淋巴细胞有效，但由于其间接促进血管形成、促进抗原呈递和影响肿瘤细胞代谢从而影响其浸润，因此巨噬细胞在TME中是重要的介质。巨噬细胞受复杂的调控网络控制，既独立又作为TME的一部分。广泛的研究导致了对这些网络和驱动巨噬细胞活动的分子机制的全面和详细的理解的发展。巨噬细胞与TME之间的相互作用显著影响肿瘤的发生和进展，使巨噬细胞成为癌症治疗的一个有希望的靶点。在这篇综述中，我们讨论了巨噬细胞在TME中极化的潜在因素，巨噬细胞在TME中的关键作用，巨噬细胞的关键转录调节因子，以及针对巨噬细胞在癌症治疗中的新策略。

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引用次数: 0