Cellular immunology最新文献_第3页

Complement system component 3 deficiency modulates the phenotypic profile of murine macrophages 补体系统成分 3 缺乏可调节小鼠巨噬细胞的表型特征

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-10-22 DOI: 10.1016/j.cellimm.2024.104886

Tiago Francisco da Silva , Thaís Akemi Amamura , Iuri Cordeiro Valadão , Milena Carvalho Carneiro , Vanessa Morais Freitas , Ana Paula Lepique , Lourdes Isaac

The Complement System is composed of more than 40 proteins that act in innate and adaptive immunity. C3 is the most abundant one and C3-deficient patients are more susceptible to recurrent and severe infections. Several studies have demonstrated the importance of C3 in controlling infections. However, its role in leukocyte biology is still poorly understood. This study aimed to evaluate several cellular parameters in macrophages from C3-deficient mice and compare them to similar cells from wild-type counterparts. We observed that in the absence of C3, the population of F4/80^low macrophages in the peritoneal cavity of thioglycolate-treated mice is diminished, probably due to the lack of chemotactic factors like C3a and low levels of C5a. Using fluorescence microscopy analysis, we observed that macrophages from C3-deficient mice exhibited morphological alterations when compared to similar cells from wild-type mice. We observed a significant increase in the expression of CD11c, which is part of CR4 (CD11c/CD18), in macrophages from C3-deficient compared to cells from wild-type mice. Treatment with 12-o-tetradecanoylphorbol-13-acetate, stimulated ROS production and MAPK activation by macrophages. However, these parameters were lower in macrophages from C3-deficient mice when compared to wild-type counterparts. In addition, the phagocytosis of iC3b-opsonized Zymosan particles was diminished in macrophages from C3-deficient mice. Our results suggest that C3 deficiency in C57Black/6 mice may influence specific morphological and functional parameters of macrophages, cells of fundamental importance for both the innate and acquired immune responses.

补体系统由 40 多种蛋白质组成，在先天性免疫和适应性免疫中发挥作用。C3 是其中含量最高的一种，缺乏 C3 的患者更容易反复发生严重感染。多项研究证明了 C3 在控制感染方面的重要性。然而，人们对其在白细胞生物学中的作用仍知之甚少。本研究旨在评估 C3 缺乏小鼠巨噬细胞的几个细胞参数，并将其与野生型小鼠的类似细胞进行比较。我们观察到，在缺乏 C3 的情况下，巯基乙酸盐处理的小鼠腹腔中的低 F4/80 巨噬细胞数量会减少，这可能是由于缺乏 C3a 等趋化因子以及 C5a 水平较低的缘故。通过荧光显微镜分析，我们观察到 C3 缺陷小鼠的巨噬细胞与野生型小鼠的类似细胞相比发生了形态学改变。我们观察到，与野生型小鼠的细胞相比，C3缺陷小鼠巨噬细胞中作为CR4（CD11c/CD18）一部分的CD11c的表达明显增加。用 12-o-tetradecanoylphorbol-13-acetate 处理可刺激巨噬细胞产生 ROS 和激活 MAPK。然而，与野生型小鼠相比，C3缺陷小鼠的巨噬细胞中这些参数较低。此外，C3缺陷小鼠的巨噬细胞对iC3b-冲淡的Zymosan颗粒的吞噬能力也有所下降。我们的研究结果表明，C57Black/6小鼠的C3缺乏症可能会影响巨噬细胞的特定形态和功能参数，而巨噬细胞对先天性免疫反应和获得性免疫反应都至关重要。

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引用次数: 0

IL-10: A Key Regulator and potential therapeutic target in uveitis IL-10：葡萄膜炎的关键调节因子和潜在治疗靶点。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-10-18 DOI: 10.1016/j.cellimm.2024.104885

Chengzhi Liu, Xinyu Wang, Xusheng Cao

Uveitis is a prevalent inflammatory eye disease that primarily affects working-age individuals and can lead to blindness if untreated. Interleukin-10 (IL-10) is a multifunctional cytokine with broad immunosuppressive properties and plays a significant role in various pathological and physiological processes. However, its specific role and underlying mechanisms in uveitis remain incompletely understood. This review aims to shed light on the biological characteristics of IL-10, its involvement in the uveitis pathophysiology, and its potential as a novel therapeutic target. By examining existing literature, the review analyzes IL-10 expression levels and regulatory mechanisms in different types of uveitis, discussing its role in immune regulation. Despite IL-10 being expressed variably across various forms of autoimmune uveitis, studies consistently highlight its protective role, prompting research into ways to enhance its bioavailability in the eye. IL-10 is often upregulated in infectious uveitis, contributing to pathogen immune evasion. Furthermore, primary intraocular lymphoma (PIOL), which shares clinical similarities with uveitis, also shows upregulated IL-10 levels, whereas IL-6 is more commonly elevated in uveitis. This differential expression suggests that IL-6 and IL-10 could be diagnostic markers to distinguish between PIOL and uveitis. Future research should continue to focus on elucidating the molecular mechanisms of IL-10 in uveitis, exploring its potential therapeutic applications, and developing targeted treatments that leverage the immunomodulatory effects of IL-10 to prevent and manage this sight-threatening condition.

葡萄膜炎是一种常见的炎症性眼病，主要影响工作年龄段的人，如不及时治疗可导致失明。白细胞介素-10（IL-10）是一种多功能细胞因子，具有广泛的免疫抑制特性，在各种病理和生理过程中发挥着重要作用。然而，人们对其在葡萄膜炎中的具体作用和潜在机制仍不甚了解。本综述旨在阐明IL-10的生物学特性、其在葡萄膜炎病理生理学中的参与及其作为新型治疗靶点的潜力。通过研究现有文献，综述分析了IL-10在不同类型葡萄膜炎中的表达水平和调节机制，讨论了它在免疫调节中的作用。尽管IL-10在各种类型的自身免疫性葡萄膜炎中的表达各不相同，但研究始终强调它的保护作用，促使人们研究如何提高它在眼内的生物利用率。在传染性葡萄膜炎中，IL-10 常常上调，有助于病原体的免疫逃避。此外，与葡萄膜炎临床相似的原发性眼内淋巴瘤（PIOL）也显示出 IL-10 水平的上调，而 IL-6 在葡萄膜炎中更常见的是升高。这种不同的表达表明，IL-6 和 IL-10 可以作为诊断标志物来区分 PIOL 和葡萄膜炎。未来的研究应继续关注阐明葡萄膜炎中IL-10的分子机制，探索其潜在的治疗应用，并开发能利用IL-10免疫调节作用的靶向治疗方法，以预防和控制这种威胁视力的疾病。

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引用次数: 0

House dust mite allergen directly activates ILC2 cells via the TLR4 signaling pathway in allergic airway diseases 在过敏性气道疾病中，屋尘螨过敏原通过 TLR4 信号通路直接激活 ILC2 细胞。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-10-18 DOI: 10.1016/j.cellimm.2024.104884

Yan Li , Zhennan Qu , Xue Wang , Qiqi Wang , Zhe Lv , Wei Wang , Sun Ying , Luo Zhang , Feng Lan

Background

Unlike T cells and B cells, the activation process of group 2 innate lymphoid cells (ILC2s) is mainly driven by epithelial cell derived cytokines rather than specific antigen recognition. Whether antigens have a direct role in activating ILC2s remains poorly understood.

Methods

Following stimulation, type 2 cytokine secretions and cell death were assessed in house dust mite (HDM)-stimulated ILC2s. To investigate the underlying mechanisms, RNA-sequencing (RNA-seq) was performed on HDM-stimulated ILC2s. The validation experiments were done through in vitro stimulation assays and an HDM-induced asthmatic murine model, using specific inhibitors targeting receptor and relevant proteins of signaling pathways.

Results

HDM stimulation increased the secretion of IL-5 and IL-13 cytokines from ILC2s, inhibited apoptosis of ILC2, and promoted the proliferation of ILC2s. As confirmed by RNA-seq, HDM stimulation upregulated genes in ILC2s, including those responsible for type 2 cytokines, ILC2s-specific transcriptional factors, and related receptors. Both toll-like receptor (TLR) 1 and TLR4 were constitutively expressed on ILC2s, however, only TLR4 was predominantly upregulated upon HDM stimulation. TAK242, a specific TLR4 inhibitor, significantly blocked the effect of HDM on ILC2s, in terms of type 2 cytokine secretions and cell death. Using specific inhibitors in pathways, we confirmed that HDM promoted ILC2s activation via TLR4-ERK, p38, and NF-κB signaling pathways.

Conclusions

Allergen HDM directly activates ILC2s through TLR4 mediated-ERK/p38/NF-κB signaling pathway. These findings provide new insights into how antigens propagate type 2 immune response via ILC2s, contributing to chronic inflammations in allergic airway diseases.

背景：与 T 细胞和 B 细胞不同，第 2 组先天性淋巴细胞（ILC2s）的活化过程主要由上皮细胞衍生的细胞因子驱动，而非特异性抗原识别。抗原在激活 ILC2s 的过程中是否起直接作用，目前还不十分清楚：方法：在刺激后，评估了家尘螨（HDM）刺激的 ILC2 的 2 型细胞因子分泌和细胞死亡情况。为了研究其潜在机制，对受HDM刺激的ILC2s进行了RNA测序（RNA-seq）。利用针对受体和信号通路相关蛋白的特异性抑制剂，通过体外刺激试验和HDM诱导的哮喘小鼠模型进行了验证实验：结果：HDM刺激增加了ILC2分泌IL-5和IL-13细胞因子，抑制了ILC2的凋亡，促进了ILC2的增殖。RNA-seq证实，HDM刺激上调了ILC2的基因，包括负责2型细胞因子、ILC2特异性转录因子和相关受体的基因。ILC2上的toll样受体（TLR）1和TLR4都是组成型表达的，但在HDM刺激下，只有TLR4主要上调。TLR4特异性抑制剂TAK242能显著阻止HDM对ILC2的影响，包括2型细胞因子的分泌和细胞死亡。通过使用通路中的特异性抑制剂，我们证实了HDM通过TLR4-ERK、p38和NF-κB信号通路促进了ILC2s的活化：结论：过敏原 HDM 可通过 TLR4 介导的 ERK/p38/NF-κB 信号通路直接激活 ILC2。这些发现为了解抗原如何通过 ILC2s 传播 2 型免疫反应、导致过敏性气道疾病中的慢性炎症提供了新的视角。

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引用次数: 0

B cell-intrinsic IFN-γ promotes excessive CD11c+ age-associated B cell differentiation and compromised germinal center selection in lupus mice 狼疮小鼠体内的 B 细胞内源性 IFN-γ 促进了 CD11c+ 年龄相关 B 细胞的过度分化，并损害了生殖中心的选择能力

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-10-18 DOI: 10.1016/j.cellimm.2024.104883

Shujun Liu , Wenqian Zhang , Shihao Tian , Yan Zhang , Zhinan Yin , Gonghua Huang , Huihui Zhang , Fubin Li

CD11c⁺ age-associated B cells (ABCs) have emerged as a key component in protective and autoreactive B cell responses. Lupus is an autoimmune disorder linked to reduced efficacy of vaccines and increased susceptibility to infections. Previously, we reported that excessive CD11c⁺ ABCs not only significantly contribute to autoantibody production but also promote aberrant T cell activation and compromised affinity-based germinal center selection in response to immunization in lupus mice. Yet, the regulation of CD11c⁺ ABC differentiation is not fully understood. In this study, we show that B cell-intrinsic IFN-γ is required for excessive CD11c⁺ ABC differentiation in lupus mice. B cell-intrinsic IFN-γ is mainly produced by CD11c⁺ ABCs. IFN-γ-deficiency leads to decreased expression of ABC characteristic genes. We further show that ablating IFN-γ can normalize T cell overactivation and rescue antigen-specific GC responses in lupus mice. Our study offers insight into the crucial role of B cell-intrinsic IFN-γ in promoting excessive CD11c⁺ ABC differentiation, which compromises affinity-based germinal center selection and affinity maturation in lupus, providing a potential strategy to normalize vaccine responses in lupus.

CD11c+ 年龄相关 B 细胞（ABC）已成为保护性和自反应性 B 细胞反应的关键组成部分。红斑狼疮是一种自身免疫性疾病，与疫苗效力降低和感染易感性增加有关。以前，我们曾报道过，过多的 CD11c+ ABCs 不仅能显著促进自身抗体的产生，还能促进狼疮小鼠异常的 T 细胞活化，并影响其对免疫的亲和性生殖中心选择。然而，CD11c+ ABC分化的调控机制尚未完全明了。本研究表明，狼疮小鼠 CD11c+ ABC 过度分化需要 B 细胞内源性 IFN-γ。B 细胞内源性 IFN-γ 主要由 CD11c+ ABCs 产生。IFN-γ缺乏会导致ABC特征基因的表达减少。我们进一步发现，消减 IFN-γ 可使狼疮小鼠的 T 细胞过度激活恢复正常，并挽救抗原特异性 GC 反应。我们的研究深入揭示了B细胞内源性IFN-γ在促进CD11c+ ABC过度分化中的关键作用，它损害了狼疮中基于亲和力的生殖中心选择和亲和力成熟，为狼疮疫苗反应正常化提供了一种潜在的策略。

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引用次数: 0

Unveiling the impact of TREM-2+ Macrophages in metabolic disorders 揭示 TREM-2+ 巨噬细胞在代谢紊乱中的影响。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-10-04 DOI: 10.1016/j.cellimm.2024.104882

Mike Telemaco Contreras Colmenares, Amanda de Oliveira Matos, Pedro Henrique dos Santos Dantas, José Rodrigues do Carmo Neto, Marcelle Silva-Sales, Helioswilton Sales-Campos

The Triggering Receptor Expressed on Myeloid cells 2 (TREM-2) has been widely known by its anti-inflammatory activity. It can be activated in response to microbes and tissue damage, leading to phagocytosis, autophagy, cell polarization and migration, counter inflammation, and tissue repair. So far, the receptor has been largely explored in neurodegenerative disorders, however, a growing number of studies have been investigating its contribution in different pathological conditions, including metabolic diseases, in which (resident) macrophages play a crucial role. In this regard, TREM-2 + macrophages have been implicated in the onset and development of obesity, atherosclerosis, and fibrotic liver disease. These macrophages can be detected in the brain, white adipose tissue, liver, and vascular endothelium. In this review we discuss how different murine models have been demonstrating the ability of such cells to contribute to tissue and body homeostasis by phagocytosing cellular debris and lipid structures, besides contributing to lipid homeostasis in metabolic diseases. Therefore, understanding the role of TREM-2 in metabolic disorders is crucial to expand our current knowledge concerning their immunopathology as well as to foster the development of more targeted therapies to treat such conditions.

髓系细胞上表达的触发受体 2（TREM-2）因其抗炎活性而广为人知。它可以在微生物和组织损伤时被激活，导致吞噬、自噬、细胞极化和迁移、对抗炎症和组织修复。迄今为止，该受体主要用于研究神经退行性疾病，然而，越来越多的研究正在调查它在不同病理条件下的贡献，包括代谢性疾病，其中（常驻）巨噬细胞发挥着至关重要的作用。在这方面，TREM-2 + 巨噬细胞与肥胖、动脉粥样硬化和纤维化肝病的发生和发展有关。这些巨噬细胞可在大脑、白色脂肪组织、肝脏和血管内皮中检测到。在这篇综述中，我们将讨论不同的小鼠模型是如何证明这些细胞除了在代谢性疾病中促进脂质平衡外，还能通过吞噬细胞碎片和脂质结构促进组织和机体的平衡。因此，了解 TREM-2 在代谢性疾病中的作用，对于扩展我们目前对代谢性疾病免疫病理学的了解以及促进开发更有针对性的疗法来治疗这类疾病至关重要。

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引用次数: 0

Netosis and trained immunity in tick-borne diseases: a possible pathogenetic role 蜱传疾病中的净毒和训练有素的免疫力：可能的致病作用。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-10-02 DOI: 10.1016/j.cellimm.2024.104881

Giusto Davide Badami , Bartolo Tamburini , Leila Mohammadnezhad , Rita Vaz-Rodrigues , Lidia La Barbera , José de la Fuente , Guido Sireci

Various types of pathogens transmitted by ticks elicit distinct immune responses just like the emerging α-Gal syndrome that is associated with allergic reactions to tick bites. The mechanisms of Neutrophil Extracellular Traps release (called NETosis) and trained immunity in response to tick-borne microbes have not been extensively investigated. In our paper, we explored the intricate interplay of NETosis and trained immunity within the realm of infectious diseases triggered by tick bites and their possible pathogenetic role in autoimmunity. We conducted an extensive literature search to identify studies for this review, considering articles and reviews published in English within the last years. Additionally, we scrutinized the references of all included papers and relevant review articles to ensure comprehensive coverage. We shed light on a plausible correlation between these innate immune responses and their potential implication in certain pathological conditions, with a specific focus on some autoimmune diseases. These findings offer new perspectives for a more profound comprehension of the immunopathogenesis of certain autoimmune-like signs where clinicians should include Tick-Borne Diseases (TBDs) in their differential diagnoses, in those geographical areas of tick infestation.

蜱虫传播的各种病原体会引起不同的免疫反应，就像新出现的α-Gal综合征一样，这种综合征与蜱虫叮咬过敏反应有关。中性粒细胞胞外捕获器的释放机制（称为NETosis）以及应对蜱传微生物的训练有素的免疫机制尚未得到广泛研究。在我们的论文中，我们探讨了由蜱虫叮咬引发的传染病领域中NETosis和训练有素的免疫力之间错综复杂的相互作用，以及它们在自身免疫中可能起到的致病作用。我们进行了广泛的文献检索，以确定本综述的研究内容，并考虑了过去几年中发表的英文文章和综述。此外，我们还仔细研究了所有收录论文和相关综述文章的参考文献，以确保全面覆盖。我们揭示了这些先天性免疫反应之间的合理相关性及其在某些病理条件下的潜在影响，特别关注一些自身免疫性疾病。这些发现提供了新的视角，有助于临床医生更深刻地理解某些自身免疫性症状的免疫发病机制，在蜱虫肆虐的地区，临床医生应将蜱传疾病（TBDs）纳入鉴别诊断中。

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引用次数: 0

Evaluation of TNF-α and IFN-γ primed conditioned medium of mesenchymal stem cell in acetic acid-induced mouse model of acute colitis 间充质干细胞TNF-α和IFN-γ条件培养基在醋酸诱导的急性结肠炎小鼠模型中的应用评估

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-09-24 DOI: 10.1016/j.cellimm.2024.104876

Manizhe Faghih , Mona Moshiri , Nader Mazrouei Arani , Fatemeh Ahmadzadeh , Narjes Jafari , Maryam Ghasemi , Saeid Abediankenari

IBD, an autoimmune-inflammatory disorder that affects people who are genetically prone to inflammation. There is a lot of interest in MSC-CM therapy, especially when primed with TNF-α + IFN-γ. Throughout the study, data were collected on the percentage of apoptotic cells, gene expression of ZO-1, Foxp3, GATA3, IDO-1, Muc2, T-bet, Notch1, TNFR2, and ROR-γt, colon weight and length, histopathological analysis, and DAI. TNF-α and IL-10 levels were assessed in addition to the NO level. The results suggest that primed MSC-CM improved DAI, mucosal deterioration, intestinal inflammation and NO concentration. The amount of TNF-α was decreased, but IL-10 and the colon’s percentage of apoptotic cells was increased. The mRNA expression of ZO-1, Foxp3, GATA3, IDO-1, and Muc2 genes increased greatly in the treatment groups, while the expression of T-bet, Notch1, TNFR2, and ROR-γt genes has decreased. These studies suggest that primed MSC-CM may combine with common treatments to improve responsiveness.

肠易激综合征是一种自身免疫炎症性疾病，易发于遗传性炎症患者。间充质干细胞-间充质干细胞疗法备受关注，尤其是在使用 TNF-α + IFN-γ 的情况下。在整个研究过程中，我们收集了凋亡细胞的百分比、ZO-1、Foxp3、GATA3、IDO-1、Muc2、T-bet、Notch1、TNFR2 和 ROR-γt 的基因表达、结肠重量和长度、组织病理学分析和 DAI 等数据。除 NO 水平外，还评估了 TNF-α 和 IL-10 水平。结果表明，间充质干细胞-CM能改善DAI、粘膜恶化、肠道炎症和NO浓度。TNF-α的含量降低了，但IL-10和结肠凋亡细胞的百分比增加了。治疗组中 ZO-1、Foxp3、GATA3、IDO-1 和 Muc2 基因的 mRNA 表达量大幅增加，而 T-bet、Notch1、TNFR2 和 ROR-γt 基因的表达量减少。这些研究表明，引诱间充质干细胞-间充质干细胞可与普通治疗方法相结合，提高反应性。

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引用次数: 0

Embracing multiple infection models to tackle Q fever: A review of in vitro, in vivo, and lung ex vivo models 采用多种感染模型应对 Q 热：体外、体内和肺部体外模型综述。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-09-24 DOI: 10.1016/j.cellimm.2024.104880

R. Marena Guzman, Daniel E. Voth

Multiple animal and cell culture models are employed to study pathogenesis of Coxiella burnetii, the causative agent of acute and chronic human Q fever. C. burnetii is a lung pathogen that is aerosolized in contaminated products and inhaled by humans to cause acute disease that can disseminate to other organs and establish chronic infection. Cellular models of Q fever include a variety of tissue-derived cell lines from mice and humans such as lung alveolar ex vivo cells. These models have the advantage of being cost-effective and reproducible. Similarly, animal models including mice and guinea pigs are cost-effective, although only immunocompromised SCID mice display a severe disease phenotype in response to Nine Mile I and Nine Mile II isolates of C. burnetii while immunocompetent guinea pigs display human-like symptoms and robust immune responses. Non-human primates such as macaques and marmosets are the closest model of human disease but are costly and largely used for adaptive immune response studies. All animal models are used for vaccine development but many differences exist in the pathogen’s ability to establish lung infection when considering infection routes, bacterial isolates, and host genetic background. Similarly, while cellular models are useful for characterization of host-pathogen mechanisms, future developments should include use of a lung infection platform to draw appropriate conclusions. Here, we summarize the current state of the C. burnetii lung pathogenesis field by discussing the contribution of different animal and cell culture models and include suggestions for continuing to move the field forward.

我们采用多种动物和细胞培养模型来研究人类急性和慢性 Q 热的病原体烧伤蜱的致病机理。烧伤弧菌是一种肺部病原体，在受污染的产品中经气溶胶扩散，被人类吸入后引起急性疾病，并可扩散到其他器官，形成慢性感染。Q热的细胞模型包括来自小鼠和人类的各种组织衍生细胞系，如肺肺泡体外细胞。这些模型具有成本效益高和可重复的优点。同样，包括小鼠和豚鼠在内的动物模型也具有成本效益，不过只有免疫功能低下的 SCID 小鼠才会对 Nine Mile I 和 Nine Mile II 分离物的烧伤弧菌表现出严重的疾病表型，而免疫功能正常的豚鼠则会表现出类似人类的症状和强大的免疫反应。猕猴和狨猴等非人灵长类动物是最接近人类疾病的模型，但成本高昂，主要用于适应性免疫反应研究。所有动物模型都可用于疫苗开发，但考虑到感染途径、细菌分离物和宿主遗传背景，病原体建立肺部感染的能力存在许多差异。同样，虽然细胞模型有助于描述宿主-病原体机制，但未来的发展应包括使用肺部感染平台来得出适当的结论。在此，我们通过讨论不同动物和细胞培养模型的贡献，总结了烧伤桿菌肺部致病机理领域的现状，并提出了继续推动该领域发展的建议。

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引用次数: 0

Neutralization of TLR2 in combination with either TNF-α or IL-1β antibody reduces the severity of septic arthritis through STAT3/mTOR signalling in lymphocytes 中和 TLR2 与 TNF-α 或 IL-1β 抗体相结合，可通过淋巴细胞中的 STAT3/mTOR 信号减轻化脓性关节炎的严重程度。

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-09-18 DOI: 10.1016/j.cellimm.2024.104878

Rituparna Ghosh, Biswadev Bishayi

Staphylococcus aureus induced Septic arthritis is considered a medical concern. S.aureus binds TLR2 to induce an array of inflammatory responses. Generation of pro-inflammatory cytokines induces T cell responses and control Th17/Treg cell balance. Regulation of T cell-mediated immunity in response to inflammation is significantly influenced by mTOR. Presence of elevated TNF-α, IL-1β decreases Treg cell activity through STAT3/mTOR, promoting proliferation of T cells towards Th17 cells. Therefore, we postulated, neutralizing TLR2 with either TNF-α or IL-1β in combination could be useful in modifying Th17/Treg cell ratio in order to treat septic arthritis by suppressing expression of mTOR/STAT3. To date, no studies have reported effects of neutralization of TLR2 along with either TNF-α or IL-1β on amelioration of arthritis correlating with mTOR/STAT3 expression. Contribution of T lymphocytes collected from blood, spleen, synovial tissues, their derived cytokines IFN-γ, IL-6, IL-17, TGF-β, IL-10 were noted. Expression of TLR2, TNFR1, TNFR2, NF-κB along with mTOR/STAT3 also recorded. Neutralization of TLR2 along with TNF-α and IL-1β were able to shift Th17 cells into immunosuppressive Treg cells. Furthermore,elevated expression of IL-10, TNFR2 and demoted expression of mTOR/ STAT3 along with NF-κB in lymphocytes confirms its role in resolution of arthritis. It was also effective in reducing oxidative stress via increasing expression of the antioxidant enzymes. As a result, it can be inferred that Treg-derived IL-10, which may mitigate inflammatory effects of septic arthritis by influencing the mTOR/STAT3 interaction in lymphocytes, may be selected as a different therapeutic strategy for reducing the impact of septic arthritis.

金黄色葡萄球菌诱发的化脓性关节炎被认为是一个医学问题。金黄色葡萄球菌与 TLR2 结合，诱发一系列炎症反应。促炎细胞因子的产生会诱导 T 细胞反应并控制 Th17/Treg 细胞的平衡。T 细胞介导的免疫对炎症反应的调节在很大程度上受 mTOR 的影响。TNF-α、IL-1β的升高会通过STAT3/mTOR降低Treg细胞的活性，促进T细胞向Th17细胞增殖。因此，我们推测，TNF-α或IL-1β联合中和TLR2可通过抑制mTOR/STAT3的表达，改变Th17/Treg细胞的比例，从而治疗化脓性关节炎。迄今为止，还没有研究报道中和TLR2与TNF-α或IL-1β对改善与mTOR/STAT3表达相关的关节炎的效果。从血液、脾脏、滑膜组织中收集的 T 淋巴细胞及其衍生细胞因子 IFN-γ、IL-6、IL-17、TGF-β、IL-10 的贡献被记录下来。还记录了 TLR2、TNFR1、TNFR2、NF-κB 以及 mTOR/STAT3 的表达。中和 TLR2 以及 TNF-α 和 IL-1β 能够使 Th17 细胞转变为免疫抑制性 Treg 细胞。此外，淋巴细胞中 IL-10、TNFR2 表达的升高和 mTOR/ STAT3 及 NF-κB 表达的降低也证实了它在缓解关节炎方面的作用。通过增加抗氧化酶的表达，它还能有效减少氧化应激。因此可以推断，Treg衍生的IL-10可通过影响淋巴细胞中mTOR/STAT3的相互作用来减轻化脓性关节炎的炎症影响，可被选为减轻化脓性关节炎影响的不同治疗策略。

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引用次数: 0

Exploration of immunomodulatory mechanism of caprine Wharton’s jelly derived mesenchymal stem cells 探索黄羊沃顿果冻间充质干细胞的免疫调节机制

IF 3.7 4区医学 Q2 CELL BIOLOGY

Cellular immunology

Pub Date : 2024-09-17 DOI: 10.1016/j.cellimm.2024.104879

Indu Baiju , Mukesh Kumar Bharti , Anjali Somal , Sriti Pandey , Irfan A. Bhat , Anand Joseph , Vikash Chandra , G. Taru Sharma

The present study was aimed to explore the possible mechanisms by which caprine Wharton’s jelly-derived MSCs (WJ-MSCs) perform their immunomodulatory function. WJ-MSCs were isolated through explants culture and characterized as per ISCT criteria using culture behavior, expression of surface markers by PCR, FACS and immunocytochemical localization (ICC), trilineage differentiation potential etc. Secretory behavior for important biomolecules (IDO, TGFβ1, VEGF, IL6) was evaluated by ICC and western blot assay. Cell-to-cell communication was studied by culturing cells in cell–cell contact and trans-well system. The MSCs when co-cultured with activated Tc and Th cells, down-regulation of T cell cytokine as well as upregulation of immunomodulatory factors (VEGF A, IL10, IL6, IDO, iNOS, PTGS2, HGF, TGFβ, CXCL10, CXCL11) was noticed in both cell–cell contact and trans-well culture system which was significantly higher in cell–cell contact system. Trilineage differentiation of MSCs showed significant upregulation of MHC I (CAHI) and MHC II (CLA DRB3) molecules suggesting better clinical applications of MSCs without differentiation to avoid immune rejection. It can be concluded that WJ-MSCs perform their immunomodulation through the secretion of a battery of biomolecules and work in both cell–cell contact manner and through their secretome.

本研究旨在探索黄羊沃顿果冻衍生间充质干细胞（WJ-MSCs）发挥其免疫调节功能的可能机制。研究人员通过外植体培养分离出 WJ-间充质干细胞，并根据 ISCT 标准对其培养行为、PCR、FACS 和免疫细胞化学定位（ICC）表面标志物的表达、三系分化潜能等进行了表征。重要生物大分子（IDO、TGFβ1、VEGF、IL6）的分泌行为通过 ICC 和 Western 印迹检测进行评估。通过细胞-细胞接触和跨孔系统培养细胞，研究了细胞间的交流。当间叶干细胞与活化的 Tc 细胞和 Th 细胞共培养时，T 细胞细胞因子下调，免疫调节因子（VEGF A、IL10、IL6、IDO、iNOS、PTGS2、HGF、TGFβ、CXCL10、CXCL11）上调，而细胞接触培养体系中的上调率明显更高。间充质干细胞的三系分化显示出 MHC I（CAHI）和 MHC II（CLA DRB3）分子的显著上调，这表明无需分化的间充质干细胞能更好地应用于临床，以避免免疫排斥反应。由此可以得出结论，WJ-间充质干细胞通过分泌一系列生物大分子，并以细胞-细胞接触方式和通过其分泌组发挥免疫调节作用。

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