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Prevention of experimental autoimmune encephalomyelitis by targeting 6-sulfo sialyl Lewis X glycans involved in lymphocyte homing. 通过靶向参与淋巴细胞归巢的 6-sulfo sialyl Lewis X 聚糖预防实验性自身免疫性脑脊髓炎。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-27 DOI: 10.1093/intimm/dxae009
Qianqian Liu, Wei Xiong, Sachiyo Obara, Hirohito Abo, Hiroko Nakatsukasa, Hiroto Kawashima

Lymphocyte homing to peripheral lymph nodes (PLN) is critical for immune surveillance. However, autoimmune diseases such as multiple sclerosis (MS) can occur due to excessive immune responses in the PLN. Here we show that 6-sulfo sialyl Lewis X (6-sulfo sLex) glycans on high endothelial venules that function as ligands for l-selectin on lymphocytes play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST)-1 and GlcNAc6ST-2 double-knockout mice lacking the expression of 6-sulfo sLeX glycans, the EAE symptoms and the numbers of effector Th1 and Th17 cells in the draining lymph nodes (dLN) and spinal cords (SC) were significantly reduced. To determine whether 6-sulfo sLeX could serve as a target for MS, we also examined the effects of anti-glycan monoclonal antibody (mAb) SF1 against 6-sulfo sLeX in EAE. Administration of mAb SF1 significantly reduced EAE symptoms and the numbers of antigen-specific effector T cells in the dLN and SC in association with suppression of critical genes including Il17a and Il17f that are involved in the pathogenesis of EAE. Taken together, these results suggest that 6-sulfo sLeX glycan would serve as a novel target for MS.

淋巴细胞归巢到外周淋巴结(PLN)对于免疫监视至关重要。然而,多发性硬化症(MS)等自身免疫性疾病的发生可能是由于外周淋巴结的过度免疫反应。我们在这里发现,内皮高位静脉上的 6-sulfo sialyl Lewis X(6-sulfo sLex)聚糖是淋巴细胞上 L 选择素的配体,在多发性硬化症的动物模型实验性自身免疫性脑脊髓炎(EAE)的发病机制中起着关键作用。在缺乏6-sulfo sLeX聚糖表达的N-乙酰葡糖胺-6-O-磺基转移酶(GlcNAc6ST)-1和GlcNAc6ST-2双基因敲除小鼠中,EAE症状以及引流淋巴结(dLN)和脊髓(SC)中Th1和Th17效应细胞的数量明显减少。为了确定 6-sulfo sLeX 是否可作为多发性硬化症的靶点,我们还研究了抗糖单克隆抗体(mAb)SF1 对 6-sulfo sLeX 在 EAE 中的作用。给予 mAb SF1 能明显减轻 EAE 症状,减少 dLN 和 SC 中抗原特异性效应 T 细胞的数量,同时抑制参与 EAE 发病机制的关键基因(包括 Il17a 和 Il17f)。综上所述,这些结果表明 6-sulfo sLeX 聚糖可作为治疗多发性硬化症的新靶点。
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引用次数: 0
Causal modulation of lipid metabolism may shape the inflammatory microenvironment and potentially augment immunotherapy: a comprehensive genetic landscape revealed by Mendelian randomization analysis. 脂质代谢的因果调节可塑造炎症微环境,并有可能增强免疫疗法:孟德尔随机分析法揭示的综合基因图谱。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-27 DOI: 10.1093/intimm/dxae008
Wenjie Li, Wei Wang

Previous observational and experimental studies have suggested a relationship between statin treatments and the augmentation of immunotherapy effects; however, the causal role of statin usage in promoting antitumor immunity remains largely unexplored. Utilizing large-scale genome-wide association studies, we conducted a Mendelian Randomization (MR) analysis to examine the association between genetically proxied inhibition of the gene for 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a specific target of statins, and 524 immunotherapy-related profiles, encompassing immune cells, inflammatory cytokines, immune checkpoints, and gut microbiota. Our findings indicated a suggestive association between statin therapy and proinflammatory as well as antitumor effects; notably, inhibition of HMGCR demonstrated a robust link with increased susceptibility of various immune cell types, including basophil cells, white blood cells, eosinophil cells, neutrophil cells, activated CD8+ T cells, dendritic cells, and natural killer cells; furthermore, a causal relationship was observed between statin use and a decrease in terminal CD8+ T cells, granulocytes, monocytes, and myeloid-derived suppressor cells; genetically proxied statin usage was also significantly associated with elevated levels of proinflammatory cytokines and immunotherapy-related gut microbiota; importantly, the potential inhibition of HMGCR in influencing the response to immunotherapy was confirmed in the real-world cohorts. This study provides novel insights into the regulatory role of HMGCR inhibition in antitumor immunity, suggesting that strategies targeting HMGCR or lipid regulation may hold therapeutic potential for enhancing the efficacy of immunotherapy.

背景:以往的观察性和实验性研究表明,他汀类药物治疗与增强免疫治疗效果之间存在关系;然而,他汀类药物的使用在促进抗肿瘤免疫方面的因果作用在很大程度上仍未得到探讨。方法:利用大规模全基因组关联研究,我们进行了孟德尔随机化(MR)分析,研究他汀类药物的特异性靶点--3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)的基因代理抑制与524个免疫疗法相关特征(包括免疫细胞、炎症细胞因子、免疫检查点和肠道微生物群)之间的关联。结果我们的研究结果表明,他汀类药物治疗与促炎症和抗肿瘤作用之间存在提示性关联;特别是,抑制 HMGCR 与各种免疫细胞类型(包括嗜碱性粒细胞、白细胞、嗜酸性粒细胞、中性粒细胞、活化的 CD8+ T 细胞、树突状细胞和自然杀伤细胞)的易感性增加有密切联系;此外,还观察到他汀类药物的使用与终末 CD8+ T 细胞、粒细胞、单核细胞和髓源性抑制细胞的减少之间存在因果关系;基因替代他汀类药物的使用还与促炎细胞因子和免疫疗法相关肠道微生物群水平的升高显著相关;重要的是,HMGCR 在影响免疫疗法反应方面的潜在抑制作用在真实世界队列中得到了证实。结论:这项研究为HMGCR抑制在抗肿瘤免疫中的调节作用提供了新的见解,表明针对HMGCR或脂质调节的策略可能具有提高免疫疗法疗效的治疗潜力。
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引用次数: 0
Reprogramming T-cell metabolism to enhance adoptive cell therapies. 重编程 T 细胞新陈代谢,加强收养细胞疗法。
IF 4.8 4区 医学 Q2 IMMUNOLOGY Pub Date : 2024-04-27 DOI: 10.1093/intimm/dxae007
Meghan Kates, Samuel D Saibil

Adoptive cell therapy (ACT) is an immunotherapeutic approach that involves isolating T cells from a patient, culturing them ex vivo, then reinfusing the cells back into the patient. Although this strategy has shown remarkable efficacy in hematological malignancies, the solid-tumour microenvironment (TME) has presented serious challenges for therapy efficacy. Particularly, the TME has immunosuppressive signalling and presents a metabolically challenging environment that leads to T-cell suppression. T-cell metabolism is an expanding field of research with a focus on understanding its inherent link to T-cell function. Here, we review the current model of T-cell metabolism from naïve cells through effector and memory life stages, as well as updates to the model from recent literature. These models of metabolism have provided us with the tools and understanding to explore T-cell metabolic and mitochondrial insufficiency in the TME. We discuss manipulations that can be made to these mitochondrial and metabolic pathways to enhance the persistence of infused T cells, overcome the metabolically challenging TME and improve the efficacy of therapy in ACT models. Further understanding and investigation of the impact of metabolic pathways on T-cell performance could contribute to improving therapy efficacy for patients.

适应性细胞疗法(ACT)是一种免疫治疗方法,包括从患者体内分离出 T 细胞,对其进行体外培养,然后再将细胞回输到患者体内。虽然这种策略在血液恶性肿瘤中显示出显著疗效,但实体瘤微环境(TME)对疗效提出了严峻挑战。尤其是,实体瘤微环境具有免疫抑制信号传导作用,并提供了一个具有挑战性的代谢环境,从而导致 T 细胞抑制。T 细胞新陈代谢是一个不断扩展的研究领域,重点是了解其与 T 细胞功能的内在联系。在此,我们回顾了目前从幼稚细胞到效应细胞和记忆细胞生命阶段的 T 细胞代谢模型,以及近期文献对该模型的更新。这些新陈代谢模型为我们提供了探索 TME 中 T 细胞新陈代谢和线粒体不足的工具和认识。我们讨论了可以对这些线粒体和代谢途径进行的操作,以提高输注 T 细胞的持久性、克服代谢挑战性 TME 并改善 ACT 模型的疗效。进一步了解和研究代谢途径对 T 细胞性能的影响有助于提高患者的疗效。
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引用次数: 0
Crystal structure of the complex of CLEC12A and an antibody that interferes with binding of diverse ligands. CLEC12A 与干扰多种配体结合的抗体的复合物晶体结构。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-27 DOI: 10.1093/intimm/dxae006
Shotaro Mori, Masamichi Nagae, Sho Yamasaki

C-type lectin receptors (CLRs) are a family of pattern recognition receptors, which detect a broad spectrum of ligands via small carbohydrate-recognition domains (CRDs). CLEC12A is an inhibitory CLR that recognizes crystalline structures such as monosodium urate crystals. CLEC12A also recognizes mycolic acid, a major component of mycobacterial cell walls, and suppresses host immune responses. Although CLEC12A could be a therapeutic target for mycobacterial infection, structural information on CLEC12A was not available. We report here the crystal structures of human CLEC12A (hCLEC12A) in ligand-free form and in complex with 50C1, its inhibitory antibody. 50C1 recognizes human-specific residues on the top face of hCLEC12A CRD. A comprehensive alanine scan demonstrated that the ligand-binding sites of mycolic acid and monosodium urate crystals may overlap with each other, suggesting that CLEC12A utilizes a common interface to recognize different types of ligands. Our results provide atomic insights into the blocking and ligand-recognition mechanisms of CLEC12A and leads to the design of CLR-specific inhibitors.

C 型凝集素受体(CLR)是一种模式识别受体,通过小型碳水化合物识别结构域(CRD)检测多种配体。CLEC12A 是一种抑制性 CLR,可识别单钠尿酸盐结晶等结晶结构。CLEC12A 还能识别霉菌细胞壁的主要成分霉菌酸,并抑制宿主的免疫反应。虽然 CLEC12A 可能是霉菌感染的治疗靶点,但目前还没有关于 CLEC12A 的结构信息。我们在此报告了人类 CLEC12A 不含配体的晶体结构以及与其抑制性抗体 50C1 复合物的晶体结构。50C1 可识别 hCLEC12A CRD 顶面的人类特异残基。一项全面的丙氨酸扫描显示,霉菌酸和尿酸单钠盐晶体的配体结合位点可能相互重叠,这表明 CLEC12A 利用一个共同的界面来识别不同类型的配体。我们的研究结果从原子角度揭示了 CLEC12A 的阻断和配体识别机制,有助于设计 CLR 特异性抑制剂。
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引用次数: 0
High-throughput quantitative assessments of the chemical complementarity of celiac disease related IGH CDR3s and a gliadin epitope. 高通量定量评估乳糜泻相关 IGH CDR3 与麦胶蛋白表位的化学互补性。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-26 DOI: 10.1093/intimm/dxae025
Rahul Jain, Max Bressler, Andrea Chobrutskiy, B. Chobrutskiy, G. Blanck
The long-term value of efficient antigen discovery includes gaining insights into the variety of potential cancer neoantigens, effective vaccines lacking adverse effects, and adaptive immune receptor (IR) targets for blocking adaptive IR-antigen interactions in autoimmunity. While the preceding goals have been partially addressed via big data approaches to HLA-epitope binding, there has been little such progress in the big data setting for adaptive IR-epitope binding. This delay in progress for the latter is likely due to, among other things, the much more complicated adaptive IR repertoire in an individual compared to individual HLA alleles. Thus, results described here represent the application of an algorithm for efficient assessment of IGH CDR3-gliadin epitope interactions, with a focus on epitopes known to be associated with an immune response in celiac disease. The hydrophobic, chemical complementarity between celiac case IGH CDR3s and known celiac epitopes was found to be greater in comparison to the hydrophobic, chemical complementarity between the same celiac case IGH CDR3s and a series of control epitopes. Thus, the approaches indicated here likely offer guidance for the development of conveniently applied algorithms for antigen verification and discovery.
高效抗原发现的长期价值包括深入了解各种潜在的癌症新抗原、无不良反应的有效疫苗以及阻断自身免疫中适应性 IR 抗原相互作用的适应性免疫受体 (IR) 靶点。虽然前述目标已通过 HLA 表位结合的大数据方法得到部分实现,但在适应性 IR 表位结合的大数据设置方面却进展甚微。后者进展迟缓的原因之一可能是,与单个 HLA 等位基因相比,个体的适应性红外谱系要复杂得多。因此,本文描述的结果代表了一种算法的应用,该算法可有效评估 IGH CDR3 与扁平苔藓表位的相互作用,重点是已知与乳糜泻免疫反应相关的表位。研究发现,乳糜泻病例 IGH CDR3 与已知乳糜泻表位之间的疏水性化学互补性要高于相同乳糜泻病例 IGH CDR3 与一系列对照表位之间的疏水性化学互补性。因此,本文介绍的方法可为开发方便应用的抗原验证和发现算法提供指导。
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引用次数: 0
MyD88 in osteoclast- and osteoblast-lineages differentially controls bone remodeling in homeostasis and malaria. 破骨细胞系和成骨细胞系中的MyD88对平衡状态和疟疾中的骨重塑具有不同的控制作用。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-20 DOI: 10.1093/intimm/dxae023
Jalal Alshaweesh, Rashmi Dash, M. S. J. Lee, Pinar Kahyaoglu, Ece Erci, Mengling Xu, Julia Matsuo-Dapaah, Camila Del Rosario Zorrilla, Kubra Aykac, Suheyla Ekemen, K. Kobiyama, Ken J Ishii, C. Coban
Chronic bone loss is an under-recognized complication of malaria, the underlying mechanism of which remains incompletely understood. We have previously shown that persistent accumulation of Plasmodium products in the bone marrow leads to chronic inflammation in osteoblast (OB) and osteoclast (OC) precursors causing bone loss through MyD88, an adaptor molecule for diverse inflammatory signals. However, the specific contribution of MyD88 signaling in OB or OC precursors in malaria-induced bone loss remains elusive. To assess the direct cell-intrinsic role of MyD88 signaling in adult bone metabolism under physiological and infection conditions, we used the Lox-Cre system to specifically deplete MyD88 in the OB or OC lineages. Mice lacking MyD88 primarily in the maturing OBs showed a comparable decrease in trabecular bone density by microcomputed tomography (µCT) to that of controls after PyNL infection. In contrast, mice lacking MyD88 in OC precursors showed significantly less trabecular bone loss than controls, suggesting that malaria-mediated inflammatory mediators are primarily controlled by MyD88 in the OC lineage. Surprisingly, however, depletion of MyD88 in OB, but not in OC precursors, resulted in reduced bone mass with decreased bone formation rates in the trabecular areas of femurs under physiological conditions. Notably, IGF-1, a key molecule for OB differentiation, was significantly lower locally and systemically when MyD88 was depleted in OBs. Thus, our data demonstrate an indispensable intrinsic role for MyD88 signaling in OB differentiation and bone formation, while MyD88 signaling in OC lineages plays a partial role in controlling malaria-induced inflammatory mediators and following bone pathology. These findings may lead to the identification of novel targets for specific intervention of bone pathologies, particularly in malaria-endemic regions.
慢性骨质流失是疟疾的一种未得到充分认识的并发症,其基本机制仍不完全清楚。我们之前已经证明,疟原虫产物在骨髓中的持续积累会导致成骨细胞(OB)和破骨细胞(OC)前体的慢性炎症,从而通过MyD88(多种炎症信号的适配分子)引起骨质流失。然而,MyD88 信号在 OB 或 OC 前体中对疟疾诱导的骨质流失的具体作用仍不明确。为了评估在生理和感染条件下MyD88信号在成人骨代谢中的直接细胞内在作用,我们利用Lox-Cre系统特异性地清除了OB或OC系中的MyD88。通过微计算机断层扫描(µCT)显示,在PyNL感染后,主要在成熟的OB中缺乏MyD88的小鼠的骨小梁密度下降与对照组相当。与此相反,OC前体中缺乏MyD88的小鼠显示的骨小梁损失明显少于对照组,这表明疟疾介导的炎症介质主要由OC系中的MyD88控制。但令人惊讶的是,在生理条件下,OB(而非 OC 前体)中的 MyD88 消耗会导致骨量减少,股骨小梁区的骨形成率也会降低。值得注意的是,当OB中的MyD88被耗竭时,OB分化的关键分子IGF-1在局部和全身都明显降低。因此,我们的数据证明了MyD88信号在OB分化和骨形成中不可或缺的内在作用,而OC系中的MyD88信号则在控制疟疾诱导的炎症介质和骨病理学方面发挥部分作用。这些发现可能会为特定干预骨病理学找到新的靶点,尤其是在疟疾流行地区。
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引用次数: 0
Disruption of Post-thymic tolerance in Skin-Reactive TCR Transgenic Mice through the Interaction of Lymphopenia and Intestinal Microbiota. 淋巴细胞减少症与肠道微生物群相互作用,破坏皮肤反应性 TCR 转基因小鼠胸腺后耐受性
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-05 DOI: 10.1093/intimm/dxae018
Hodaka Hayabuchi, Yukiko Tokifuji, Hayato Takahashi, Masayuki Amagai, Akihiko Yoshimura, S. Chikuma
Autoimmune diseases often arise from conditions where the immune system is compromised. While lymphopenia-induced proliferation (LIP) is crucial for immune system development and maturation, it is also caused by environmental insult, such as infection and becomes a risk factor for autoimmunity in adults. We used Dsg3H1 TCR Transgenic mice, whose T cells are designed to recognize desmogrein-3, a skin antigen, to explore the impact of lymphopenia on post-thymic tolerance. Dsg3H1 mice are known to delete the most highly autoreactive T cells in thymus, and develop only subtle immune-mediated pathology in a steady state. However, we found that a transient lymphopenia by total body irradiation or cyclophosphamide, results in massive dermatitis in Dsg3H1 mice. The symptoms included expansion and development of self-reactive T cells, their differentiation into CD44 high IL-17 producing helper T cells, and severe neutrophilic inflammation. Repopulation of FOXP3+ T regulatory cells after lymphopenia normally occurred, suggesting escape of skin-reactive conventional T cells from control by regulatory T cell. Furthermore, we found that a depletion of the intestinal microbiota by antibiotics prevents the cyclophosphamide induced dermatitis, indicating roles of commensal intestinal microbiota in LIP and Th17 development in vivo. The current data suggested that post thymic tolerance of Dsg3H1 mice is established on a fragile balance in lymphoreplete immune environment and broken by interplay between lymphopenia and intestinal microbiota. The dynamic phenotypes observed in Dsg3H1 mice prompts a reevaluation of opportunistic lymphopenia together with microbiota as pivotal environmental factors, impacting individuals with genetic predispositions of autoimmune diseases.
自身免疫性疾病通常源于免疫系统受损。淋巴细胞减少诱导的增殖(LIP)对免疫系统的发育和成熟至关重要,但它也可由感染等环境损伤引起,并成为成人患自身免疫病的风险因素。我们利用 Dsg3H1 TCR 转基因小鼠来探讨淋巴细胞减少症对胸腺后耐受性的影响,这种小鼠的 T 细胞能识别皮肤抗原 desmogrein-3。众所周知,Dsg3H1 小鼠会删除胸腺中最高度自反应性的 T 细胞,并且在稳定状态下只会出现免疫介导的细微病变。然而,我们发现,全身照射或环磷酰胺造成的一过性淋巴细胞减少会导致 Dsg3H1 小鼠出现大规模皮炎。症状包括自我反应性 T 细胞的扩增和发展,它们分化成 CD44 高的可产生 IL-17 的辅助性 T 细胞,以及严重的中性粒细胞炎症。淋巴细胞减少后,FOXP3+ T 调节细胞的重新填充正常发生,这表明皮肤反应性常规 T 细胞摆脱了调节性 T 细胞的控制。此外,我们还发现,通过抗生素消耗肠道微生物群可以预防环磷酰胺诱导的皮炎,这表明肠道共生微生物群在体内LIP和Th17的发展中发挥作用。目前的数据表明,Dsg3H1小鼠的胸腺后耐受性是建立在淋巴细胞减少的免疫环境的脆弱平衡上的,并被淋巴细胞减少和肠道微生物群之间的相互作用所打破。在 Dsg3H1 小鼠身上观察到的动态表型促使人们重新评估机会性淋巴细胞减少症和微生物群这两个关键环境因素,它们对具有自身免疫疾病遗传倾向的个体产生影响。
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引用次数: 0
Chemoattractant receptor signaling in humoral immunity. 体液免疫中的趋化受体信号传导
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-04 DOI: 10.1093/intimm/dxae021
Taiichiro Shirai, Akiko Nakai, Kazuhiro Suzuki
Efficient induction of humoral immune responses depends on orchestrated migration of B cells within lymphoid organs, which is governed by G protein-coupled receptors (GPCRs) responding to chemoattractants, represented by chemokines. After ligand binding, GPCRs are phosphorylated by different GPCR kinases (GRKs) at distinct sites on the receptor C termini, which dictates functional outcomes of β-arrestin-mediated signaling, ranging from receptor inactivation to effector molecule activation. However, the molecular mechanisms by which individual GRKs are selectively targeted to GPCRs have been poorly understood. Our recent study revealed that a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and 8 (COMMD3/8 complex) functions as an adaptor that recruits a specific GRK to chemoattractant receptors and plays an important role in the control of B cell migration during humoral immune responses. In this review, we summarize the current understanding of chemoattractant receptor signaling in the context of humoral immunity and discuss the potential of the COMMD3/8 complex as a therapeutic target for autoimmune diseases.
体液免疫反应的有效诱导取决于 B 细胞在淋巴器官内的协调迁移,而这种迁移是由 G 蛋白偶联受体(GPCR)对趋化因子为代表的趋化吸引物做出反应所控制的。配体结合后,GPCR 在受体 C 端不同位点被不同的 GPCR 激酶(GRKs)磷酸化,这决定了 β-阿司匹林介导的信号转导的功能结果,从受体失活到效应分子激活。然而,人们对单个 GRK 选择性靶向 GPCR 的分子机制还知之甚少。我们最近的研究发现,由含铜代谢 MURR1 结构域(COMMD)3 和 8 组成的蛋白复合物(COMMD3/8 复合物)可作为一种适配体,将特定的 GRK 募集到趋化吸引受体上,并在体液免疫反应过程中控制 B 细胞迁移方面发挥重要作用。在这篇综述中,我们总结了目前对体液免疫中趋化受体信号转导的理解,并讨论了 COMMD3/8 复合物作为自身免疫疾病治疗靶点的潜力。
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引用次数: 0
TAK1-binding proteins (TAB)2 and TAB3 are redundantly required for TLR-induced cytokine production in macrophages. TAK1结合蛋白(TAB)2和TAB3是巨噬细胞产生TLR诱导的细胞因子的冗余必需蛋白。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-03 DOI: 10.1093/intimm/dxae020
Tanveer Ali, Huong Minh Nguyen, Naeem Abbas, Osamu Takeuchi, Shizuo Akira, Toshihiko Suzuki, Goro Matsuzaki, G. Takaesu
Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways downstream of diverse immune receptors, including Toll-like receptors (TLRs). Upon stimulation with TLR ligands, TAK1 is activated via recruitment to lysine 63-linked polyubiquitin chain through TAK1-binding proteins (TAB) 2 and TAB3. However, the physiological importance of TAB2 and TAB3 in macrophages is still controversial. A previous study has shown that mouse bone marrow-derived macrophages (BMDMs) isolated from mice double deficient for TAB2 and TAB3 produced tumor necrosis factor (TNF)-α and interleukin (IL)-6 to the similar levels as control wild-type BMDMs in response to TLR ligands such as lipopolysaccharide (LPS) or Pam3CSK4, indicating that TAB2 and TAB3 are dispensable for TLR signaling. In this study, we revisited the role of TAB2 and TAB3 using an improved mouse model. We observed a significant impairment in the production of pro-inflammatory cytokines and chemokine in LPS- or Pam3CSK4-treated BMDMs deficient for both TAB2 and TAB3. Double deficiency of TAB2 and TAB3 resulted in the decreased activation of NF-κB and MAPK pathways as well as the slight decrease in TAK1 activation in response to LPS or Pam3CSK4. Notably, the TLR-mediated expression of inhibitor of NF-κB (IκB)ζ was severely compromised at the protein and mRNA levels in the TAB2/TAB3 double-deficient BMDMs, thereby impeding IL-6 production. Our results suggest that TAB2 and TAB3 play a redundant and indispensable role in TLR signaling pathway.
转化生长因子-β激活激酶 1(TAK1)在先天性免疫和适应性免疫中发挥着关键作用。TAK1 对于激活包括 Toll 样受体(TLRs)在内的多种免疫受体下游的丝裂原活化蛋白激酶(MAPKs)和核因子(NF)-κB 通路至关重要。在 TLR 配体的刺激下,TAK1 通过 TAK1 结合蛋白(TAB)2 和 TAB3 与赖氨酸 63 链接的多泛素链结合而被激活。然而,TAB2 和 TAB3 在巨噬细胞中的生理重要性仍存在争议。先前的一项研究表明,在对脂多糖(LPS)或 Pam3CSK4 等 TLR 配体做出反应时,从 TAB2 和 TAB3 双缺陷小鼠体内分离出的小鼠骨髓巨噬细胞(BMDMs)产生的肿瘤坏死因子(TNF)-α 和白细胞介素(IL)-6 的水平与对照野生型 BMDMs 相近,这表明 TAB2 和 TAB3 在 TLR 信号转导中是不可或缺的。在本研究中,我们使用改进的小鼠模型重新研究了 TAB2 和 TAB3 的作用。我们观察到,在经 LPS 或 Pam3CSK4 处理的同时缺乏 TAB2 和 TAB3 的 BMDMs 中,促炎细胞因子和趋化因子的产生明显减少。TAB2和TAB3的双重缺乏导致NF-κB和MAPK通路的活化减少,以及在LPS或Pam3CSK4作用下TAK1活化的轻微减少。值得注意的是,在 TAB2/TAB3 双缺陷的 BMDMs 中,TLR 介导的 NF-κB 抑制剂(IκB)ζ 的表达在蛋白和 mRNA 水平上受到严重影响,从而阻碍了 IL-6 的产生。我们的研究结果表明,TAB2 和 TAB3 在 TLR 信号通路中发挥着不可或缺的冗余作用。
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引用次数: 0
Recent advances in the epithelial barrier theory. 上皮屏障理论的最新进展。
IF 4.4 4区 医学 Q2 Medicine Pub Date : 2024-04-03 DOI: 10.1093/intimm/dxae002
Yagiz Pat, Duygu Yazici, Paolo D'Avino, Manru Li, Sena Ardicli, Ozge Ardicli, Yasutaka Mitamura, Mübeccel Akdis, Raja Dhir, Kari Nadeau, Ioana Agache, Ismail Ogulur, Cezmi A Akdis

The epithelial barrier theory links the recent rise in chronic non-communicable diseases, notably autoimmune and allergic disorders, to environmental agents disrupting the epithelial barrier. Global pollution and environmental toxic agent exposure have worsened over six decades because of uncontrolled growth, modernization, and industrialization, affecting human health. Introducing new chemicals without any reasonable control of their health effects through these years has led to documented adverse effects, especially on the skin and mucosal epithelial barriers. These substances, such as particulate matter, detergents, surfactants, food emulsifiers, micro- and nano-plastics, diesel exhaust, cigarette smoke, and ozone, have been shown to compromise the epithelial barrier integrity. This disruption is linked to the opening of the tight-junction barriers, inflammation, cell death, oxidative stress, and metabolic regulation. Consideration must be given to the interplay of toxic substances, underlying inflammatory diseases, and medications, especially in affected tissues. This review article discusses the detrimental effect of environmental barrier-damaging compounds on human health and involves cellular and molecular mechanisms.

上皮屏障理论认为,近年来慢性非传染性疾病(尤其是自身免疫性和过敏性疾病)的增加与破坏上皮屏障的环境因素有关。六十多年来,由于无节制的增长、现代化和工业化,全球污染和环境有毒物质暴露日益严重,影响了人类健康。这些年来,在没有对新化学物质的健康影响进行合理控制的情况下引入这些物质,导致了有记录的不良影响,尤其是对皮肤和粘膜上皮屏障的影响。这些物质,如微粒物质、洗涤剂、表面活性剂、食品乳化剂、微塑料和纳米塑料、柴油废气、香烟烟雾和臭氧,已被证明会损害上皮屏障的完整性。这种破坏与紧密连接屏障的开放、炎症、细胞死亡、氧化应激和代谢调节有关。必须考虑有毒物质、潜在炎症疾病和药物的相互作用,尤其是在受影响的组织中。这篇综述文章讨论了破坏环境屏障的化合物对人体健康的有害影响,并涉及细胞和分子机制。
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International immunology
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