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Trained immunity: General and emerging concepts 训练有素的免疫力:一般概念和新概念。
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-29 DOI: 10.1111/imr.13326
Patricia Vuscan, Brenda Kischkel, Leo A. B. Joosten, Mihai G. Netea

Over the past decade, compelling evidence has unveiled previously overlooked adaptive characteristics of innate immune cells. Beyond their traditional role in providing short, non-specific protection against pathogens, innate immune cells can acquire antigen-agnostic memory, exhibiting increased responsiveness to secondary stimulation. This long-term de-facto innate immune memory, also termed trained immunity, is mediated through extensive metabolic rewiring and epigenetic modifications. While the upregulation of trained immunity proves advantageous in countering immune paralysis, its overactivation contributes to the pathogenesis of autoinflammatory and autoimmune disorders. In this review, we present the latest advancements in the field of innate immune memory followed by a description of the fundamental mechanisms underpinning trained immunity generation and different cell types that mediate it. Furthermore, we explore its implications for various diseases and examine current limitations and its potential therapeutic targeting in immune-related disorders.

在过去十年中,令人信服的证据揭示了先天性免疫细胞以前被忽视的适应性特征。先天性免疫细胞的传统作用是针对病原体提供短期、非特异性的保护,除此之外,它们还能获得抗原识别记忆,对二次刺激表现出更强的反应能力。这种长期的事实上的先天性免疫记忆,也被称为训练有素的免疫,是通过广泛的新陈代谢重新布线和表观遗传修饰介导的。训练有素的免疫力的上调在对抗免疫瘫痪方面证明是有利的,但其过度激活也是自身炎症和自身免疫性疾病的发病机制之一。在这篇综述中,我们将介绍先天性免疫记忆领域的最新进展,然后描述训练有素的免疫力产生的基本机制以及介导这种免疫力的不同细胞类型。此外,我们还探讨了先天性免疫记忆对各种疾病的影响,并研究了免疫相关疾病目前的局限性及其潜在的治疗目标。
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引用次数: 0
Signals that control MAIT cell function in healthy and inflamed human tissues 控制健康和发炎人体组织中 MAIT 细胞功能的信号。
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-22 DOI: 10.1111/imr.13325
Andrew J. Konecny, Yin Huang, Manu Setty, Martin Prlic

Mucosal-associated invariant T (MAIT) cells have a semi-invariant T-cell receptor that allows recognition of antigen in the context of the MHC class I-related (MR1) protein. Metabolic intermediates of the riboflavin synthesis pathway have been identified as MR1-restricted antigens with agonist properties. As riboflavin synthesis occurs in many bacterial species, but not human cells, it has been proposed that the main purpose of MAIT cells is antibacterial surveillance and protection. The majority of human MAIT cells secrete interferon-gamma (IFNg) upon activation, while some MAIT cells in tissues can also express IL-17. Given that MAIT cells are present in human barrier tissues colonized by a microbiome, MAIT cells must somehow be able to distinguish colonization from infection to ensure effector functions are only elicited when necessary. Importantly, MAIT cells have additional functional properties, including the potential to contribute to restoring tissue homeostasis by expression of CTLA-4 and secretion of the cytokine IL-22. A recent study provided compelling data indicating that the range of human MAIT cell functional properties is explained by plasticity rather than distinct lineages. This further underscores the necessity to better understand how different signals regulate MAIT cell function. In this review, we highlight what is known in regards to activating and inhibitory signals for MAIT cells with a specific focus on signals relevant to healthy and inflamed tissues. We consider the quantity, quality, and the temporal order of these signals on MAIT cell function and discuss the current limitations of computational tools to extrapolate which signals are received by MAIT cells in human tissues. Using lessons learned from conventional CD8 T cells, we also discuss how TCR signals may integrate with cytokine signals in MAIT cells to elicit distinct functional states.

粘膜相关不变性 T 细胞(MAIT)具有一种半不变性 T 细胞受体,可在 MHC I 类相关蛋白(MR1)的背景下识别抗原。核黄素合成途径的代谢中间产物已被确定为具有激动特性的 MR1 限制性抗原。由于核黄素合成发生在许多细菌物种中,但不发生在人体细胞中,因此有人认为 MAIT 细胞的主要作用是抗菌监测和保护。大多数人类 MAIT 细胞在激活后会分泌γ 干扰素(IFNg),而组织中的一些 MAIT 细胞也能表达 IL-17。鉴于 MAIT 细胞存在于被微生物群定植的人体屏障组织中,MAIT 细胞必须能够以某种方式区分定植和感染,以确保只在必要时激发效应功能。重要的是,MAIT 细胞还具有其他功能特性,包括可能通过表达 CTLA-4 和分泌细胞因子 IL-22 来帮助恢复组织稳态。最近的一项研究提供了令人信服的数据,表明人类 MAIT 细胞功能特性的范围是由可塑性而非独特的血统所决定的。这进一步强调了更好地了解不同信号如何调控 MAIT 细胞功能的必要性。在这篇综述中,我们将重点介绍目前已知的 MAIT 细胞激活和抑制信号,并特别关注与健康和炎症组织相关的信号。我们考虑了这些信号对 MAIT 细胞功能的数量、质量和时间顺序,并讨论了目前计算工具在推断 MAIT 细胞在人体组织中接收哪些信号方面的局限性。利用从传统 CD8 T 细胞中学到的经验,我们还讨论了 TCR 信号如何与 MAIT 细胞中的细胞因子信号相结合,从而激发出不同的功能状态。
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引用次数: 0
Correction to “The anti-inflammatory and antiviral properties of anionic pulmonary surfactant phospholipids” 更正 "阴离子肺表面活性物质磷脂的抗炎和抗病毒特性"。
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-21 DOI: 10.1111/imr.13320

Numata M, Kandasamy P, Voelker DR. The anti-inflammatory and antiviral properties of anionic pulmonary surfactant phospholipids. Immunol Rev. 2023; 317: 166–186. doi:10.1111/imr.13207

In the article, the second paragraph was inadvertently added to Summary section and should have been removed.

The Summary reads:

The minor anionic pulmonary surfactant phospholipids, POPG and PI, exhibit anti-inflammatory effects as antagonists for multiple TLRs. These lipids also have strong efficacies as antivirals against multiple respiratory RNA-enveloped viruses such as RSV, IAVs, and SARS-CoV-2. PI also has a potent effect against non-enveloped virus (human rhinovirus A). These lipids also have very strong potential to be applied as anti-inflammatory compounds for acute lung injury, induced by cytokine storms, including severe COVID-19.

We determined the antiviral efficacy of POPG against five clinical isolates of RSV (designated by GenBank accession numbers) and recombinant strains of RSV (rA2-A2F, rA2-19F, and rA2 Long F) in comparison with RSV-A2.12 The titer of each strain is shown as PFU/mL, and the efficacies of POPG and POPC (200 μg/mL) on each strain are stated as the viral titers by plaque assays. Data are shown as means ± SD from two independent experiments.

The Summary should read:

The minor anionic pulmonary surfactant phospholipids, POPG and PI, exhibit anti-inflammatory effects as antagonists for multiple TLRs. These lipids also have strong efficacies as antivirals against multiple respiratory RNA-enveloped viruses such as RSV, IAVs, and SARS-CoV-2. PI also has a potent effect against non-enveloped virus (human rhinovirus A). These lipids also have very strong potential to be applied as anti-inflammatory compounds for acute lung injury, induced by cytokine storms, including severe COVID-19.

We apologize for this error.

Numata M, Kandasamy P, Voelker DR.阴离子肺表面活性磷脂的抗炎和抗病毒特性。Immunol Rev. 2023; 317: 166-186.doi:10.1111/imr.13207在文章中,摘要部分不慎添加了第二段,应予以删除。摘要如下:次要阴离子肺表面活性磷脂 POPG 和 PI 作为多种 TLR 的拮抗剂表现出抗炎作用。作为抗病毒药物,这些磷脂对多种呼吸道 RNA 病毒(如 RSV、IAV 和 SARS-CoV-2)也有很强的疗效。PI 对无包膜病毒(人鼻病毒 A)也有很强的抑制作用。这些脂质还具有很强的潜力,可用作细胞因子风暴(包括严重的 COVID-19)诱发的急性肺损伤的抗炎化合物。我们测定了 POPG 对五种 RSV 临床分离株(以 GenBank 编号命名)和 RSV 重组株(rA2-A2F、rA2-19F 和 rA2 Long F)的抗病毒效力,并与 RSV-A2 进行了比较12。每种毒株的滴度以 PFU/mL 表示,POPG 和 POPC(200 μg/mL)对每种毒株的效力以斑块检测的病毒滴度表示。数据以两个独立实验的平均值±标度表示。摘要应为:小阴离子肺表面活性磷脂 POPG 和 PI 作为多种 TLR 的拮抗剂,具有抗炎作用。作为抗病毒药物,这些磷脂对多种呼吸道 RNA 病毒(如 RSV、IAV 和 SARS-CoV-2)也有很强的疗效。PI 对无包膜病毒(人鼻病毒 A)也有很强的抑制作用。这些脂质还具有很强的潜力,可用作细胞因子风暴(包括严重的 COVID-19)诱发的急性肺损伤的抗炎化合物。
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引用次数: 0
New insights into ILC2 memory 对 ILC2 记忆的新认识
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-20 DOI: 10.1111/imr.13323
Itziar Martinez-Gonzalez, Fumio Takei

Group 2 Innate Lymphoid Cells (ILC2s) are innate lymphocytes involved in type 2 immunity. ILC2s are abundant at the barrier tissues and upon allergen exposure, respond to epithelial-derived alarmins by producing type 2 cytokines (e.g., IL-5 and IL-13). Upon activation, some of these activated ILC2s acquire immunological memory and can mount enhanced responses upon further allergen encounters. Here, we review recent findings of the cellular and molecular mechanisms underlying immune memory in ILC2s both in mice and humans and discuss the implications of memory ILC2s in the context of allergic diseases.

第 2 组先天性淋巴细胞(ILC2s)是参与第 2 类免疫的先天性淋巴细胞。ILC2 在屏障组织中含量丰富,一旦接触过敏原,就会通过产生 2 型细胞因子(如 IL-5 和 IL-13)对上皮源性 alarmins 做出反应。激活后,其中一些活化的 ILC2 会获得免疫记忆,并在进一步接触过敏原时产生更强的反应。在此,我们回顾了小鼠和人类 ILC2 免疫记忆的细胞和分子机制的最新发现,并讨论了记忆 ILC2 对过敏性疾病的影响。
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引用次数: 0
Extrinsic and intrinsic drivers of natural killer cell clonality 自然杀伤细胞克隆的内在和外在驱动因素
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-20 DOI: 10.1111/imr.13324
Timo Rückert, Chiara Romagnani

Clonal expansion of antigen-specific lymphocytes is the fundamental mechanism enabling potent adaptive immune responses and the generation of immune memory. Accompanied by pronounced epigenetic remodeling, the massive proliferation of individual cells generates a critical mass of effectors for the control of acute infections, as well as a pool of memory cells protecting against future pathogen encounters. Classically associated with the adaptive immune system, recent work has demonstrated that innate immune memory to human cytomegalovirus (CMV) infection is stably maintained as large clonal expansions of natural killer (NK) cells, raising questions on the mechanisms for clonal selection and expansion in the absence of re-arranged antigen receptors. Here, we discuss clonal NK cell memory in the context of the mechanisms underlying clonal competition of adaptive lymphocytes and propose alternative selection mechanisms that might decide on the clonal success of their innate counterparts. We propose that the integration of external cues with cell-intrinsic sources of heterogeneity, such as variegated receptor expression, transcriptional states, and somatic variants, compose a bottleneck for clonal selection, contributing to the large size of memory NK cell clones.

抗原特异性淋巴细胞的克隆扩增是产生强效适应性免疫反应和免疫记忆的基本机制。伴随着明显的表观遗传学重塑,单个细胞的大量增殖产生了控制急性感染的临界效应细胞,以及防止未来遇到病原体的记忆细胞池。最近的研究表明,对人类巨细胞病毒(CMV)感染的先天性免疫记忆是通过自然杀伤(NK)细胞的大规模克隆扩增来稳定维持的,这就提出了在没有重新排列抗原受体的情况下克隆选择和扩增机制的问题。在这里,我们结合适应性淋巴细胞克隆竞争的机制来讨论克隆 NK 细胞记忆,并提出了可能决定先天性淋巴细胞克隆成功与否的替代选择机制。我们提出,外部线索与细胞内在异质性来源(如受体表达、转录状态和体细胞变异)的整合构成了克隆选择的瓶颈,导致了记忆性 NK 细胞克隆的巨大规模。
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引用次数: 0
Cancer immunity by tissue-resident type 1 innate lymphoid cells and killer innate-like T cells 组织驻留的 1 型先天性淋巴细胞和杀伤性先天性类 T 细胞对癌症的免疫作用。
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-20 DOI: 10.1111/imr.13319
Jing Zhang, Albert M. Li, Emily R. Kansler, Ming O. Li

Cancer progression can be restrained by tumor-infiltrating lymphocytes in a process termed cancer immunosurveillance. Based on how lymphocytes are activated and recruited to the tumor tissue, cancer immunity is either pre-wired, in which innate lymphocytes and innate-like T cells are directly recruited to and activated in tumors following their differentiation in primary lymphoid organs; or priming-dependent, in which conventional adaptive T cells are first primed by cognate antigens in secondary lymphoid organs before homing to and reactivated in tumors. While priming-dependent cancer immunity has been a focus of cancer immunology research for decades, in part due to historical preconception of cancer theory and tumor model choice as well as clinical success of conventional adaptive T cell-directed therapeutic programs, recent studies have revealed that pre-wired cancer immunity mediated by tissue-resident type 1 innate lymphoid cells (ILC1s) and killer innate-like T cells (ILTCKs) is an integral component of the cancer immunosurveillance process. Herein we review the distinct ontogenies and cancer-sensing mechanisms of ILC1s and ILTCKs in murine genetic cancer models as well as the conspicuously conserved responses in human malignancies. How ILC1s and ILTCKs may be targeted to broaden the scope of cancer immunotherapy beyond conventional adaptive T cells is also discussed.

肿瘤浸润淋巴细胞可抑制癌症进展,这一过程被称为癌症免疫监视。根据淋巴细胞被激活并被招募到肿瘤组织的方式,癌症免疫要么是预接线的,即先天性淋巴细胞和类先天性 T 细胞在原发性淋巴器官分化后直接被招募到肿瘤并被激活;要么是引物依赖的,即传统的适应性 T 细胞首先被继发性淋巴器官中的同源抗原引物激活,然后才归巢到肿瘤并被重新激活。尽管部分由于癌症理论和肿瘤模型选择的历史先入为主以及传统适应性T细胞导向治疗方案的临床成功,启动依赖型癌症免疫几十年来一直是癌症免疫学研究的重点,但最近的研究发现,由组织驻留的1型先天性淋巴细胞(ILC1s)和杀伤性先天性类T细胞(ILTCKs)介导的预接线癌症免疫是癌症免疫监视过程中不可或缺的组成部分。在此,我们回顾了 ILC1s 和 ILTCKs 在小鼠遗传癌症模型中不同的本体和癌症感应机制,以及在人类恶性肿瘤中明显保守的反应。我们还讨论了如何针对 ILC1s 和 ILTCKs 扩大癌症免疫疗法的范围,使其超越传统的适应性 T 细胞。
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引用次数: 0
Early life imprinting of intestinal immune tolerance and tissue homeostasis 肠道免疫耐受和组织稳态的早期生命印记
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-19 DOI: 10.1111/imr.13321
Yoselin A. Paucar Iza, Chrysothemis C. Brown

Besides its canonical role in protecting the host from pathogens, the immune system plays an arguably equally important role in maintaining tissue homeostasis. Within barrier tissues that interface with the external microenvironment, induction of immune tolerance to innocuous antigens, such as commensal, dietary, and environmental antigens, is key to establishing immune homeostasis. The early postnatal period represents a critical window of opportunity in which parallel development of the tissue, immune cells, and microbiota allows for reciprocal regulation that shapes the long-term immunological tone of the tissue and subsequent risk of immune-mediated diseases. During early infancy, the immune system appears to sacrifice pro-inflammatory functions, prioritizing the establishment of tissue tolerance. In this review, we discuss mechanisms underlying early life windows for intestinal tolerance with a focus on newly identified RORγt+ antigen-presenting cells–Thetis cells–and highlight the role of the intestinal microenvironment in shaping intestinal immune system development and tolerance.

免疫系统除了在保护宿主免受病原体侵害方面发挥典型作用外,还在维持组织稳态方面发挥着同样重要的作用。在与外部微环境相接的屏障组织内,诱导对无害抗原(如共生、饮食和环境抗原)的免疫耐受是建立免疫稳态的关键。出生后早期是一个关键的机会之窗,在这一时期,组织、免疫细胞和微生物群的平行发展可实现相互调节,从而形成组织的长期免疫学基调以及免疫介导疾病的后续风险。在婴儿早期,免疫系统似乎会牺牲促炎功能,优先建立组织耐受性。在这篇综述中,我们将以新发现的 RORγt+ 抗原递呈细胞--Thetis 细胞为重点,讨论生命早期肠道耐受性窗口的内在机制,并强调肠道微环境在塑造肠道免疫系统发育和耐受性中的作用。
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引用次数: 0
Group 3 innate lymphoid cells: A trained Gutkeeper 第 3 组先天性淋巴细胞训练有素的守门员
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-16 DOI: 10.1111/imr.13322
Nicolas Serafini, James P. Di Santo

Group 3 innate lymphoid cells (ILC3s) are tissue-resident immune lymphocytes that critically regulate intestinal homeostasis, organogenesis, and immunity. ILC3s possess the capacity to “sense” the inflammatory environment within tissues, especially in the context of pathogen challenges that imprints durable non-antigen-specific changes in ILC3 function. As such, ILC3s become a new actor in the emerging field of trained innate immunity. Here, we summarize recent discoveries regarding ILC3 responses to bacterial challenges and the role these encounters play in triggering trained innate immunity. We further discuss how signaling events throughout ILC3 ontogeny potentially control the development and function of trained ILC3s. Finally, we highlight the open questions surrounding ILC3 “training” the answers to which may reveal new insights into innate immunity. Understanding the fundamental concepts behind trained innate immunity could potentially lead to the development of new strategies for improving immunity-based modulation therapies for inflammation, infectious diseases, and cancer.

第 3 组先天性淋巴细胞(ILC3s)是组织驻留免疫淋巴细胞,对肠道稳态、器官生成和免疫起着至关重要的调节作用。ILC3 具有 "感知 "组织内炎症环境的能力,尤其是在病原体挑战的背景下,这种挑战会在 ILC3 功能中留下持久的非抗原特异性变化的印记。因此,ILC3s 成为训练有素的先天性免疫这一新兴领域的新角色。在此,我们总结了最近发现的 ILC3 对细菌挑战的反应,以及这些遭遇在触发训练有素的先天性免疫中所起的作用。我们进一步讨论了信号事件如何在整个 ILC3 本体发育过程中潜在地控制训练有素的 ILC3 的发育和功能。最后,我们强调了围绕 ILC3 "训练 "的开放性问题,这些问题的答案可能会揭示先天性免疫的新见解。了解训练有素的先天性免疫背后的基本概念,有可能开发出新的策略,改善基于免疫的炎症、传染病和癌症调节疗法。
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引用次数: 0
Epigenetic control of microglial immune responses 小胶质细胞免疫反应的表观遗传控制
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-16 DOI: 10.1111/imr.13317
Rebekka Scholz, Desirée Brösamle, Xidi Yuan, Marc Beyer, Jonas J. Neher

Microglia, the major population of brain-resident macrophages, are now recognized as a heterogeneous population comprising several cell subtypes with different (so far mostly supposed) functions in health and disease. A number of studies have performed molecular characterization of these different microglial activation states over the last years making use of “omics” technologies, that is transcriptomics, proteomics and, less frequently, epigenomics profiling. These approaches offer the possibility to identify disease mechanisms, discover novel diagnostic biomarkers, and develop new therapeutic strategies. Here, we focus on epigenetic profiling as a means to understand microglial immune responses beyond what other omics methods can offer, that is, revealing past and present molecular responses, gene regulatory networks and potential future response trajectories, and defining cell subtype-specific disease relevance through mapping non-coding genetic variants. We review the current knowledge in the field regarding epigenetic regulation of microglial identity and function, provide an exemplary analysis that demonstrates the advantages of performing joint transcriptomic and epigenomic profiling of single microglial cells and discuss how comprehensive epigenetic analyses may enhance our understanding of microglial pathophysiology.

小胶质细胞是驻留在大脑中的巨噬细胞的主要群体,现已被认为是一个异质群体,由多种细胞亚型组成,在健康和疾病中具有不同的功能(迄今为止大多是假定的功能)。在过去几年中,许多研究利用 "omics "技术,即转录组学、蛋白质组学以及较少见的表观基因组学分析,对这些不同的小胶质细胞活化状态进行了分子表征。这些方法为确定疾病机制、发现新的诊断生物标志物和开发新的治疗策略提供了可能性。在这里,我们将重点放在表观遗传学分析上,将其作为了解小胶质细胞免疫反应的一种手段,超越其他全息方法所能提供的范围,即揭示过去和现在的分子反应、基因调控网络和潜在的未来反应轨迹,并通过绘制非编码基因变异图来定义细胞亚型特异性疾病相关性。我们回顾了该领域有关小胶质细胞特性和功能的表观遗传调控的现有知识,提供了一项示范性分析,展示了对单个小胶质细胞进行联合转录组学和表观遗传学分析的优势,并讨论了全面的表观遗传学分析可如何增进我们对小胶质细胞病理生理学的了解。
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引用次数: 0
Metabolic regulation of type I interferon production I 型干扰素产生的代谢调节。
IF 8.7 2区 医学 Q1 Medicine Pub Date : 2024-03-11 DOI: 10.1111/imr.13318
Shane M. O'Carroll, Fiona D. R. Henkel, Luke A. J. O'Neill

Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function in health and disease, establishing the field of immunometabolism. Specifically, pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and those involving lipid metabolism have been implicated in regulating immune cell function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about how metabolic changes regulate interferon responses. Interferons are critical cytokines in host defense, rapidly induced upon pathogen recognition, but are also involved in autoimmune diseases. This review summarizes how metabolic change impacts interferon production. We describe how glycolysis, lipid metabolism (specifically involving eicosanoids and cholesterol), and the TCA cycle-linked intermediates itaconate and fumarate impact type I interferons. Targeting these metabolic changes presents new therapeutic possibilities to modulate type I interferons during host defense or autoimmune disorders.

在过去十年中,有关代谢途径如何调节免疫细胞在健康和疾病中的功能的发现激增,从而建立了免疫代谢领域。具体来说,糖酵解、三羧酸(TCA)循环等途径以及涉及脂质代谢的途径都与调节免疫细胞功能有关。病毒感染会引起免疫代谢变化,从而导致抗病毒免疫,但人们对代谢变化如何调节干扰素反应知之甚少。干扰素是宿主防御的关键细胞因子,能在识别病原体时迅速诱导,但也与自身免疫性疾病有关。本综述总结了代谢变化如何影响干扰素的产生。我们描述了糖酵解、脂质代谢(特别是涉及二十烷酸和胆固醇的代谢)以及与 TCA 循环相关的中间产物它康酸和富马酸如何影响 I 型干扰素。针对这些代谢变化提供了新的治疗可能性,可在宿主防御或自身免疫性疾病期间调节 I 型干扰素。
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引用次数: 0
期刊
Immunological Reviews
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